Clinical trial NCT04698915
Conditions: SBRT Borderline Resectable Pancreatic Cancer Unresectable Pancreatic Cancer
Sponsor: Galera Therapeutics, Inc.
Start date: 2021-05-07; Completion date: 2023-11-30
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GTI-4711-201 is designed as a Phase 2b, multicenter, randomized, double-blind, placebo-controlled study to determine the effect to OS by adding GC4711 to SBRT following chemotherapy in patients with unresectable or borderline resectable nonmetastatic

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Drug GC4711 intervention 2: Placebo
Intervention descriptions: intervention 1: 15 Minute IV Infusion intervention 2: 15 Minute IV Infusion

Protocol documents:
Prot_SAP_000.pdf: 
Protocol GTI-4711-201 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
GRECO-2: A Randomized, Phase 2b Study of Stereotactic 
Body Radiation Therapy (SBRT) in combination with GC4711 
in the Treatment of Unresectable or Borderline Resectable, 
Nonmetastatic Pancreatic Cancer 
Protocol Number: 
GTI-4711-201 
Compound: 
GC4711 
Sponsor  
Sponsor 
Name: 
Galera Therapeutics Inc. 
Legal 
Registered 
Address: 
45 Liberty Blvd, Suite 230, Malvern, PA 19355 
Regulatory Agency 
Identifier Number(s) 
152586 
 
 
Protocol Date: 
Document Version 
Date 
Amendment 6.0 
08 OCT 2023 
 
 
 
 
 
 
CONFIDENTIALITY NOTICE 
The information contained in this protocol and all other information relevant to GC4711 are the 
confidential and proprietary information of Galera Therapeutics Inc. and, except as may be 
required by federal, state, or local laws or regulation, may not be disclosed to others without the 
prior written permission of Galera Therapeutics Inc. 


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Study Acknowledgement 
GRECO-2: A Randomized, Phase 2b Study of Stereotactic Body Radiation Therapy (SBRT) in 
combination with GC4711 in the Treatment of Unresectable or Borderline Resectable, 
Nonmetastatic Pancreatic Cancer  
This protocol has been approved by Galera Therapeutics, Inc. The following signature documents 
this approval. 
 
J. Mel Sorensen, MD  
Chief Executive Officer 
Galera Therapeutics, Inc. 
Investigator Statement 
I have read the attached protocol and agree to abide by all provisions set forth therein. I will provide 
copies of the protocol and other pertinent information to all individuals responsible to me who will 
assist with the study. 
I agree to comply with the International Conference on Harmonisation, Tripartite Guideline on Good 
Clinical Practice (ICH, GCP) in accordance with local government and applicable global and local 
government regulations/guidelines for example 21 Code of Federal Regulations (CFR) Parts 11, 50, 
54, 56, and 312. 
I agree to ensure that Financial Disclosure Statements will be completed before study initiation, 
during the studies if there are changes that affect my financial disclosure status, and one year after 
study completion by: 
· 
myself (including, if applicable, my spouse [or legal partner] and dependent children) 
· 
my sub investigators (including, if applicable, their spouses [or legal partners] and dependent 
children) 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Galera Therapeutics. 
The Sponsor or its designee will have access to source documentation from which case report forms 
have been completed. 
 
__________________________________ 
__________________________ 
Signature of Principal Investigator 
Date (DD MMM YYYY) 
 
__________________________________ 
Printed Name of Principal Investigator 


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TABLE OF CONTENTS 
CONTENTS 
TABLE OF CONTENTS ........................................................3 
1 
CLINICAL STUDY SYNOPSIS ..............................................8 
2 
INTRODUCTION .........................................................23 
2.1 
Radiotherapy for Unresectable or Borderline Resectable Pancreatic Cancer ..........23 
2.2 
Investigational Medicinal Product ..........................................24 
2.3 
Pilot clinical data with GC4711 analogue GC4419 .............................26 
2.4 
GC4711 Nonclinical Safety Data ...........................................28 
2.5 
GC4711 Clinical Development .............................................28 
2.6 
Rationale for Present Trial ................................................30 
3 
OBJECTIVES AND ENDPOINTS ............................................30 
3.1 
Rationale for Primary Endpoint ............................................30 
4 
STUDY DESIGN .........................................................32 
4.1 
Overall Design .........................................................32 
4.2 
Study Duration for Participants ............................................33 
4.3 
Replacement of Participants ...............................................34 
4.4 
End of Study Definitions .................................................34 
4.5 
Rationale for SBRT Regimen ..............................................34 
4.6 
Rationale for GC4711 Dose and Schedule ....................................35 
5 
STUDY POPULATION ....................................................35 
5.1 
Eligibility Criteria .......................................................35 
5.2 
Screen Failures .........................................................37 
5.3 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ..............................................37 
6 
STUDY INTERVENTION ..................................................38 
6.1 
Investigational Product: GC4711 ...........................................38 
 
Dosage Formulation and Preparation .....................................38 
 
GC4711 Dosage, Administration, and Schedule ............................38 
 
GC4711 Handling/Storage/Accountability .................................39 
 
GC4711 Drug Packaging and Labeling ...................................39 
 
Maintenance of the Blind ..............................................39 
 
Investigational Product Storage .........................................40 
 
Study Intervention Compliance .........................................40 
6.2 
Concomitant Medications .................................................40 


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6.3 
Drug Interactions .......................................................40 
 
CYP2D6 Substrates ..................................................40 
 
OCT2, MATE1 and MATE2-K Transporters ...............................41 
6.4 
Prohibited Medications ...................................................41 
6.5 
Anticipated toxicities ....................................................42 
 
Anticipated Toxicities of GC4711 .......................................42 
 
Toxicity Management/Infusion Modifications ..............................43 
 
Anticipated Toxicities of SBRT .........................................43 
 
Anticipated Complications of Surgery ....................................45 
 
Anticipated Complications of Chemotherapy ...............................45 
 
Chemotherapy dosing adjustments .......................................45 
7 
STEREOTACTIC BODY RADIATION THERAPY (SBRT) .......................46 
7.1 
SBRT Principles ........................................................46 
7.2 
Treatment schedule ......................................................46 
7.3 
Quality Review .........................................................46 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................47 
8.1 
Imaging protocols .......................................................47 
 
CT imaging .........................................................47 
 
MRI imaging ........................................................48 
8.2 
Efficacy Assessments ....................................................48 
 
Definitions for Response Evaluation .....................................48 
8.3 
Safety Assessments ......................................................50 
 
Physical Examinations ................................................50 
 
Vital Signs ..........................................................50 
 
Electrocardiograms ...................................................50 
8.4 
Adverse Events and Serious Adverse Events ..................................50 
 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information ...........................................50 
 
Method of Detecting Adverse Events and Serious Adverse Events ..............51 
 
Follow-up of Adverse Events and Serious Adverse Events ....................51 
 
Regulatory Reporting Requirements for Serious Adverse Events ...............51 
 
Pregnancy ..........................................................51 
 
Late Toxicities ......................................................52 
 
Treatment of Overdose ................................................52 
 
Misuse/Abuse .......................................................52 
8.5 
Pharmacokinetics .......................................................52 


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9 
STATISTICAL CONSIDERATIONS .........................................53 
9.1 
Sample Size Calculation ..................................................53 
9.2 
Randomization/Blinding ..................................................53 
9.3 
Analysis Populations .....................................................54 
9.4 
Analysis of the Primary Endpoint ...........................................54 
 
Definition of Primary Endpoint .........................................54 
 
Method of Analysis ...................................................55 
 
Handling of Intercurrent Events .........................................55 
 
Handling of Missing Values/Censoring/Discontinuations .....................55 
 
Sensitivity and Supportive Analyses .....................................55 
9.5 
Analysis of Key Secondary Endpoint ........................................56 
 
Method of analysis of PFS .............................................56 
 
Handling of intercurrent events for PFS ...................................56 
 
Handling of Missing Values/Censoring/Discontinuations for PFS ..............56 
 
Sensitivity and Supportive Analyses .....................................56 
9.6 
Other endpoints .........................................................57 
9.7 
Data Monitoring Committee (DMC) ........................................57 
 
DMC Interim Safety Analysis ..........................................57 
 
DMC Interim Efficacy Analysis .........................................58 
9.8 
Significant Toxicities ....................................................58 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....59 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................59 
 
Regulatory and Ethical Considerations ....................................59 
 
Financial Disclosure ..................................................59 
 
Informed Consent Process .............................................60 
 
Data Protection ......................................................60 
 
Data Quality Assurance ...............................................61 
 
Source Documents ...................................................61 
 
Start and Closure of Study and/or Sites ...................................61 
 
Publication Policy ....................................................62 
APPENDIX 1: Clinical Laboratory Tests ...........................................63 
APPENDIX 2: RECIST 1.1 Tumor Response Evaluation ..............................64 
APPENDIX 3: Reporting Guideline for Pancreas Imaging by CT and MRI ................65 
APPENDIX 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................67 
Definition of Adverse Event .....................................................67 


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Definition of Serious Adverse Event ..............................................68 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events ..............69 
Reporting of SAEs ............................................................71 
APPENDIX 5: NCCN Guidelines v1.2020- Criteria Defining Locally advanced  Versus 
Borderline Resectable PC ................................................72 
APPENDIX 6: PRO-CTCAE ....................................................73 
APPENDIX 7: Multidisciplinary Review Worksheets .................................80 
APPENDIX 8: Contraceptive Guidance and Collection of Pregnancy Information ..........83 
APPENDIX 9: Abbreviations ....................................................85 
11 REFERENCES ...........................................................89 
12 SUMMARY OF CHANGES .................................................96 
 
 


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LIST OF TABLES 
 
Table 1: Schedule of Assessments ................................................20 
Table 2a: Safety summary from pilot randomized trial GTI-4419-101 ....................27 
Table 4: Expected acute and late SBRT toxicities summarized ..........................44 
Table 5: PK Draw and ECG Windows .............................................52 
Table 6: Protocol-Required Safety Laboratory Assessments ............................63 
 
LIST OF FIGURES 
 
Figure 1: Study Design .........................................................19 
Figure 2: Subject Flow .........................................................22 
Figure 3: GC4711 Potentiated the Antitumor Effects of SBRT in a Human NSCLC Model ..25 
Figure 4: GC4711 Potentiated the Antitumor Effects of SBRT in a Human Pancreatic 
Adenocarcinoma Model ............................................26 
 
 
 


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1 CLINICAL STUDY SYNOPSIS 
Title of Study:  
GRECO-2: A Randomized, Phase 2b Study of Stereotactic Body Radiation Therapy (SBRT) 
in combination with GC4711 in the Treatment of Unresectable or Borderline Resectable 
Nonmetastatic Pancreatic Cancer  
Name of Investigational Product: 
GC4711 
Name of Sponsor/Company: 
Galera Therapeutics, Inc. 
Number of Study Centers: Approximately 40 in the United States, Canada, EU and UK 
Estimated Enrollment Period: Approximately 36 months 
Studied period:  
Estimated date first subject enrolled, Q1 2021 
Estimated date last subject completed, Q1 2027  
Phase of development: 2b 
Objectives:  
Primary: To determine the effect on overall survival (OS) of adding GC4711 to SBRT 
compared to placebo in subjects with locally advanced or borderline resectable 
nonmetastatic pancreatic cancer (PC)  
 
Secondary: To determine the effect of adding GC4711 to SBRT on: 
• Progression-free survival (PFS), locoregional control (LRC), and time to distant 
metastases (TDM). 
• Surgical resection outcomes: proportion of subjects in whom R0 or R1 resection is 
achieved; pathological response in resected specimens.  
• Overall response and in-field local response 
• Acute and late toxicity observed after SBRT  
 
Exploratory:  
• To evaluate patterns of change in CA19-9 with GC4711 + SBRT 
• To evaluate the effect of GC4711 + SBRT on patient-reported symptoms  
• To assess pharmacokinetics of GC4711 in the study population 
Rationale:  
While systemic treatment of PC has improved, surgical resection rates are low, and patients 
with borderline or unresectable nonmetastatic PC still have poor outcomes. Both toxicity and 


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disease progression during induction chemotherapy limit the number of potential candidates 
for surgery (Maggino 2019, Lambert 2019). Different neo-adjuvant approaches, including 
multi-agent chemotherapy and radiotherapy (RT), are evolving (Balaban 2016, Palta 2019); 
however, timing and dose are under continuous debate. Reports on neoadjuvant 
(chemo)radiation with a biological equivalent dose (BED) lower than 100 Gy have cited 
improved local control but not OS (Krishnan 2016, Hammel 2013, Polistina 2010, Chin 2018). 
With introduction of SBRT (also known as stereotactic ablative radiotherapy or SABR), 
motion -management tools, and overall more precise delivery techniques, RT has shifted to 
higher dose delivery (Petrelli 2017, Colbert 2018) with the goal of improving surgical 
intervention rates and overall outcomes for PC patients (Mellon 2015, Jung 2019). Use of 
SBRT regimens that employ 3-5 fractions have been reported to show an acceptable toxicity 
profile (Reyngold 2019, Palta 2019, Suker 2019, Mellon 2015, Herman 2015) and exhibited 
superior cell killing compared to conventionally fractionated RT (Zhong 2017). Online 
imaging and adaptive workflow (CT-on-rails or MRI-linac) have rendered SBRT delivery of 
BED >100 Gy for pancreatic lesions feasible and a 5 × 10 Gy regimen has demonstrated 
acceptable safety, while normal tissue constraints are preserved (Hassanzadeh 2020, 
Elhammali 2015, Reyngold 2019, Jung 2019).  
GC4711 is a novel, water-soluble, low-molecular weight, manganese-containing macrocyclic 
ligand complex that is being developed as a 15-minute intravenously (IV) administered 
treatment to be given in combination with SBRT to potentially improve efficacy and reduce 
normal tissue damage of high dose per fraction radiation delivery in local treatment of PC. 
GC4711 is a selective mimetic of superoxide dismutase (SOD) enzymes—a "dismutase 
mimetic." It converts superoxide to hydrogen peroxide, and in so doing is a potential radiation 
response-modifier that may increase both the clinical efficacy and safety of SBRT. In 
nonclinical models, the addition of selective dismutase mimetics such as GC4711 to SBRT 
regimens enhanced antitumor activity in different tumor types, including PC experimental 
xenograft mouse models (Sishc 2019, 2020).  
In a pilot Phase 1 trial (GTI-4419-101), subjects with locally advanced PC were randomized to 
receive SBRT plus either, the GC4711 analogue, GC4419, or placebo. This trial has 
demonstrated acceptable safety with SBRT (5 × 10-11 Gy), as well as apparent improvements 
in locoregional control, and time to distant metastases, PFS, and OS. GC4419 was chosen for 
the pilot study because it has the same mechanism of action as GC4711, and at the time that 
study was initiated, had already successfully completed Phase 2 trials for reduction of severe 
oral mucositis associated with Intensity-modulated radiation therapy (IMRT) (Anderson 2018, 
2019). 
Healthy human volunteer studies have demonstrated that the safety and plasma exposure to 
GC4711 and GC4419 are similar at equimolar doses administered via the same route and 
schedule. These studies further confirmed acceptable safety of repeated doses of GC4711 at an 
approximately equimolar dose as GC4419 used in the pilot trial. 
Altogether, these data support the hypothesis that GC4711 may improve the benefit-risk ratio 
of 5-fraction SBRT delivering a BED >100 Gy by improving SBRT efficacy without 
increasing toxicity to healthy surrounding tissue (e.g., bowel toxicity). 


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Methodology:  
GTI-4711-201 is designed as a Phase 2b, multicenter, randomized, double-blind, placebo-
controlled study to determine the effect on the OS of adding GC4711 to SBRT following 
chemotherapy in subjects with unresectable or borderline resectable nonmetastatic PC. 
Approximately 220 subjects will be enrolled (Figure 1: Study Design). Subjects must have 
nonmetastatic unresectable, borderline resectable PC, or refuse or be medically unfit for 
surgery for PC.  
All newly diagnosed subjects will receive at least 6 weeks of chemotherapy consisting of 
FOLFIRINOX, mFOLFIRINOX, and/or a gemcitabine-based doublet regimen (e.g., 
gemcitabine combined with nab-paclitaxel, cisplatin, capecitabine) prior to SBRT. There is no 
upper limit on the number of pre-SBRT chemotherapy cycles that a subject may receive as 
long as there is no evidence of metastatic spread during treatment with the initial 
chemotherapy regimen.  Subjects may change chemotherapy regimens prior to starting SBRT 
(but still limited to FOLFIRINOX, mFOLFIRINOX or a gemcitabine-doublet regimen) for 
issues of toxicity or intolerance per institutional practice/SOC/NCCN guidelines. Subjects 
with local progression may be included as long as they remain non-metastatic at screening.  
Subjects who commence chemotherapy with single-agent gemcitabine but who are then able 
to tolerate either a gemcitabine doublet, FOLFIRINOX or mFOLFIRINOX may also be 
included in the trial as long as they fulfill the requirements for at least 6 weeks of pre-SBRT 
combination chemotherapy with these regimens as outlined above. Other variations such as 
FOLFOX or FOLFIRI are also acceptable; any other variations must be discussed with the 
Medical Monitor prior to randomization. After at least 6 weeks of chemotherapy, subjects will 
be evaluated by computed tomography (CT) and magnetic resonance imaging (MRI) for 
SBRT feasibility and for distant disease progression; those without metastases will be 
considered for enrollment. Eligible subjects will be stratified at randomization based on 
disease status at diagnosis: borderline resectable vs unresectable (radiographically or 
medically inoperable), as determined by the site’s institutional multidisciplinary review 
following the NCCN definition v1.2020 (see Appendix 5).  
Eligible subjects will be randomized in a 1:1 ratio to receive either GC4711 100 mg or 
placebo given via IV over 15 minutes (+ 5 minutes) before each fraction of SBRT (total of 5 
doses).  
Due to the risk of a radio-sensitizing effect of fluorouracil and gemcitabine, SBRT should not 
be started until at least one week following the end of the last chemotherapy cycle. SBRT 
should start no later than 42 days following the end of the last chemotherapy cycle. Following 
SBRT (and surgery, if possible), patients may receive additional adjuvant chemotherapy at the 
discretion of the investigator, and according to standard of care, institutional practice, and 
NCCN guidelines, as applicable.   
Full details of protocol requirements for SBRT can be found in the Radiation Therapy Quality 
Assurance (RTQA) Manual.  The RTQA Manual will establish requirements and expectations 


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for radiation therapy planning (including required contours, contouring guidelines and 
dosimetric criteria) and radiation therapy delivery (including simulation, motion assessment, 
motion management and image guidance).  SBRT will be delivered as 5 fractions of 10 Gy 
prescribed to the residual gross tumor volume (GTV) including perineural and vascular 
invasion and 3mm margin to the clinical target volume (CTV) to at least 30 Gy, while 
respecting normal tissue constraints; no elective nodal fields will be given, only macroscopic 
areas will be treated. SBRT fractions should be given with MR or CT-image guidance, 
matching both target and avoidance structures, confirming respect of constraints. 
Each participating center should provide SBRT certification. Additional training will be 
provided by the designated Radiotherapy Quality Assurance Group, and all radiation treatment 
plans will be centrally reviewed (see RTQA Manual).  The first two radiotherapy planning 
case submissions from each site will be reviewed and approved prior to treatment. Subsequent 
radiotherapy plans will be submitted and reviewed retrospectively. All SBRT treatments will 
be reviewed to evaluate compliance with treatment guidelines and sites will receive case 
review reports that document case review results, findings and recommendations. 
SBRT fractions will be given sequentially, and within 180 minutes from the end of the 
GC4711 or placebo infusion. Between fractions, a minimum of 18 hours and a maximum of 
72 hours are permitted. Additionally, an occasional 96-hour window is acceptable (i.e. in case 
of a holiday or machine breakdown). All 5 fractions should be given within 10 calendar days. 
If a subject is unable to receive their treatment within 10 days, the Medical Monitor and 
Galera study team should be notified.  
After SBRT, subjects judged by the site’s institutional multidisciplinary review to be 
technically unresectable on CT/MRI (Appendix 5) or medically inoperable may receive 
additional chemotherapy at the discretion of the investigator, and according to standard of 
care, institutional practice, and NCCN guidelines, as applicable.  All chemotherapy treatment 
should be documented in the source and electronic case report forms.  
Those subjects judged by the site’s institutional multidisciplinary review or medical team to be 
technically and medically operable after SBRT will be surgically explored within 8 weeks 
following SBRT, and outcomes of margins and pathology will be collected. Following 
surgery, additional chemotherapy may be administered at the discretion of the investigator, 
and according to standard of care, institutional practice, and NCCN guidelines, as applicable.  
All chemotherapy treatment should be documented in the source and electronic case report 
forms.   
All subjects will be followed for survival and efficacy every 3 months from the completion of 
SBRT for 2 years and every 6 months after, for a total of 3 years. Late toxicity will be 
followed for the first year or until distant disease progression.  In the event of documented 
progressive distant disease, subjects will move to survival follow-up only.  


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For efficacy end points (PFS, LRC, TDM), CT-imaging will be used and centrally reviewed 
retrospectively.   
Surgical exploration and excision rates, as well as margin status and pathological response 
will be recorded for all subjects judged resectable.  
MRI will be used for SBRT eligibility (1), as well as judgement of post-SBRT technical 
resectability (2), validation by the site’s institutional multidisciplinary review will be 
documented. When MRI is contraindicated, a CT scan is acceptable if fiducials have been 
placed.  
CA19.9 values will be collected for exploratory analysis at diagnosis, screening, 4 weeks after 
SBRT and every 3 months until 1 year follow up or until local or distant documented 
progression. Patient reported outcomes will be collected through 13 months after the 
completion of  SBRT.  
Blood samples will be obtained for pharmacokinetic (PK) analyses on Day 1 prior to GC4711 
or placebo, immediately after the infusion and 24 hours after the Day 1 infusion but prior to 
the following infusion.  PK blood samples will also be obtained on Day 4 of SBRT prior to 
GC4711 or placebo, immediately after the infusion and 24 hours after the infusion on Day 4 
but prior to the following infusion. 12-lead ECGs will be performed at the same timepoints.  
An independent unblinded Data Monitoring Committee (DMC) will be convened to 
periodically review safety data as outlined in the DMC charter.  After 20 subjects have been 
randomized, the will review unblinded safety data through the 4 week visit after SBRT. At this 
analysis, the DMC will review all safety data and, if necessary, will consider a 
recommendation to temporarily suspend trial enrollment and treatment, and consider revisions 
of the study for safety, in the case where more than 4 subjects encounter a significant toxicity 
in the experimental arm than in the control per arm. Adverse events (AEs), as well as 
treatment delay in SBRT fractions, surgical exploration and chemotherapy retake will be 
monitored independently given the blinded design.  
All imaging for tumor assessment will undergo retrospective, independent central review 
(following RECIST 1:1). Local imaging assessments will be used for study eligibility and 
treatment decisions.   
Number of Subjects (planned): approximately 220 subjects (110 per arm) 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria:  
1. 
Histological or biopsy proven adenocarcinoma of the pancreas. Cytology is 
acceptable if histology cannot be obtained. 
2. 
Newly diagnosed non-metastatic PC judged by site multidisciplinary review to be 
feasible for  SBRT, as well as having measurable disease as defined by RECIST 


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1.1 (see Appendix 2) and classified following NCCN guidelines v1.2020 (see 
Appendix 5):  
a. Locally advanced and technically unresectable, as determined by the 
multidisciplinary group following the NCCN definition v1 2020 (see Appendix 5) 
b. Potentially resectable, but subject is judged not a candidate for surgery, after 
multidisciplinary review at the investigative site 
c. Potentially resectable, but the subject 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  
3. 
Completed at least 6 weeks of chemotherapy consisting of FOLFIRINOX, 
mFOLFIRINOX, and/or a gemcitabine-based doublet regimen prior to start of 
SBRT. Other variations such as FOLFOX or FOLFIRI are also acceptable; any 
other variations must be discussed with the Medical Monitor prior to 
randomization. 
4. 
Remain non-metastatic as confirmed by a CT scan at screening. 
5. 
Female or male subjects ≥ 18 years of age. 
6. 
ECOG performance status of 0-2. 
7. 
Adequate end-organ function, based on routine clinical and laboratory workup: 
a. Absolute Neutrophil Count > 1,000 µL, platelets ≥ 75,000 µL, hemoglobin ≥ 
7.0 g/dl 
b. Calculated creatinine clearance ≥ 30 ml/min 
c. Total bilirubin ≤ 2.5 × ULN , AST and ALT ≤ 3 x ULN 
d. International normalized ratio (INR) or prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving 
anticoagulant therapy,  
8. 
Males and females of childbearing potential must agree to use highly effective 
contraception (Appendix 8)starting prior to the first day of treatment and 
continuing for 30 days (females) and 90 days (males) after the last dose of GC4711 
or placebo. 
9. 
Ability to understand and the willingness to sign a written informed consent form 
(ICF). 
 
Exclusion Criteria 
1. Subjects with documented metastatic disease using standard work-up (per investigator) 
at diagnosis or at screening response evaluation  
2. First-line chemotherapy other than FOLFIRINOX, mFOLFIRINOX, and/or a 
gemcitabine-based doublet regimen.  Subjects receiving either regimen after initial  
gemcitabine monotherapy are eligible.  


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3. Prior abdominal RT with substantial overlap in radiation fields as determined by the 
treating radiation oncologist. 
4. Subjects not recovered/controlled from treatment-related toxicities judged by the local 
investigator. 
5. Uncontrolled malignancy other than PC that requires active treatment.  
6. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to GC4711. 
7. Uncontrolled gastric or duodenal ulcer disease within 30 days of dosing. 
8. Visible invasion of bulky tumor into the lumen of the bowel or stomach on endoscopy 
(Note: Radiological or superficial bowel infiltration is allowed, unless deemed 
clinically unsafe). 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection requiring delay of therapy, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the 
opinion of the investigator, would limit compliance with study requirements. 
10. Subjects with Gilbert syndrome who are known to be homozygous for the UGT1A 
polymorphism. 
11. Subjects with hypokalemia whose QT/QTc interval > 470 ms (for women) and > 450 
ms (for men) on the screening ECG at visit 
12. Treatment with any investigational drug outside this protocol since diagnosis until 
disease progression given for the disease in study.  Prior to the randomization of 
subjects on other investigational agents, Sponsor’s written approval must be obtained. 
13. 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. 
14. Female subjects who are pregnant or breastfeeding. 
15. Any other conditions that, in the investigator’s opinion, might indicate the subject to be 
unsuitable for the study. 
16. Subjects who have already undergone resection of their pancreatic tumors. 
Duration of Treatment:  
SBRT will be administered in 5 sequential fractions of 10 Gy with each fraction preceded by 1 
dose of GC4711 or placebo (total of 5 doses). All doses should be given within 10 calendar 
days.  
Reference Therapy, Dosage, and Mode of Administration:  
Study will include two treatment arms: 
• Arm A: GC4711 100 mg 15 min (+ 5 minute), 100 mL IV infusion to be completed 
within 180 minutes of the start of SBRT) administered before each SBRT from the 
first fraction of SBRT to the last fraction of SBRT. 


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• Arm B: Placebo 15 min (+ 5 minute), 100 mL normal saline IV infusion to be 
completed within 180 minutes of the start of SBRT) administered before each SBRT as 
described for Arm A. Normal saline will be provided by the site’s unblinded 
pharmacists. 
Criteria for Evaluation: 
For OS evaluation: 
• OS is defined as the time from randomization to the date of death from any cause. 
Survival data will be collected every 3 months in the first 2 years and then every 6 
months after until 3 years following protocol therapy.  Subjects not known to have died 
will be censored at the last known date the subject was known to be alive. 
For PFS, local control, locoregional control, time to distant metastases, and best tumor 
response (overall and within-field): 
• CT (chest/abdomen) using RECIST 1.1*,  
*Local progression on imaging 4 weeks after SBRT requires confirmation at the next scheduled imaging, to 
rule out early pseudo-progression after SBRT (Eisenhauer 2009; Appendix 2) 
For resection rates: 
• Multi-disciplinary review of resectability judgements and in explored subjects, margin 
(e.g., R0/R1) and pathological response (pCR, pNR, pPR, no response) status will be 
recorded.  
For toxicity/safety: 
• Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, to monitor 
adverse events (AEs/SAEs); all through 90 days post-SBRT and late toxicity until 
distant disease progression (Section 6.4, Table 3) or until 1 year post-SBRT. (CTCAE 
vs 5, 2017)  
Exploratory: 
• PRO-CTCAE pancreas to evaluate patient-reported symptoms (Basch 2014, 
Kluetz 2016,Appendix 6)  
• CA19.9 values will be recorded from diagnosis, at screening, and during the first year 
of follow-up after SBRT or until documented distant or local progression. 
Normalization is defined as < 37 U/ml. Significant decrease is estimated as >30%. 
• Plasma concentrations of GC4711 and major metabolites during 
SBRT+GC4711/placebo treatment. 
 
Safety Monitoring and Toxicity Management: 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
subject will be assessed for the development of toxicity according to the SOA (Table 1). 
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0.  
Toxicities that will require infusion modification of GC4711 or placebo include the following: 


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• Grade 2 or greater hypotension occurring within 1 hour of the end of GC4711 or 
placebo infusion. 
• Other Grade 3 or greater AEs judged by the investigator to be possibly attributable to 
the study infusion. 
Patients who experience a toxicity noted above during or shortly after the infusion of 
GC4711/placebo should have their infusion times increased to 30 minutes (+5 minutes).  
If the toxicity recurs, the infusion time should be increased to 45 minutes (+5 minutes), and 
may be increased to 60 minutes (+5 minutes) if hypotension occurs with a 45-minute infusion.  
If toxicity occurs with a 60-minute infusion, the patient should be discontinued from further 
treatment with GC4711/placebo but should remain on study for all other protocol 
interventions (SBRT) and assessments.   
Concomitant Medications/Treatments: 
Investigators may prescribe concomitant medication or supportive care as deemed necessary. 
All such medications taken, including anti-emetics, steroids, and anti-tumor treatments, as 
well as any (surgical) interventions will be recorded from 30-days prior to dosing of 
GC4711/placebo through 90 days after completion of SBRT. After the 3 Month follow up 
visit, only medications used to treat late radiation toxicities should be recorded in the subject’s 
eCRF through 1 year (or distant disease progression, whichever comes first), including 
inhalers, steroids, oxygen supply, etc. Additionally, any new anti-cancer therapy given at any 
time during follow-up should be recorded in the CRF through 36 months post-SBRT, 
including during the survival follow-up.  
Supportive care may include antiemetic prophylaxis, hematopoietic growth factor therapy as 
used per ASCO guidelines, systemic antibiotics, hydration to prevent renal damage, or other 
medications or treatments, consistent with the local standard of practice with the following 
exceptions:  
Prohibited medications/treatments: 
• Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildenafil, 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 from 1 day prior 
to dosing until at least 24 hours after the last dose of GC4711 or placebo. 
• Treatment with any investigational drug outside this protocol since diagnosis until 
disease progression given for the disease in study (e.g., chemotherapy, 
immunotherapy, targeted therapy, hormone therapy, and biologic therapy).  Prior to the 
randomization of subjects on other investigational agents, Sponsor’s written approval 
must be obtained. 
 


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Statistical Considerations: 
An independent Data Monitoring Committee (DMC) will be empaneled. 
Efficacy evaluations will be done on the intent-to-treat population of all randomized subjects. 
The primary efficacy analysis will be the comparison of OS between the two treatment groups 
using a stratified log-rank test at an overall two-sided 5% level of significance. Stratification 
will be performed at randomization based on borderline resectable versus unresectable 
disease, as documented by the site’s institutional multidisciplinary treatment team.  Medically 
inoperable subjects and subjects refusing surgery will be grouped under unresectable. The OS 
distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, 
medians, and 95% confidence intervals of the medians will be presented for each treatment 
group. The hazard ratio for OS will be estimated along with its 95% confidence interval using 
a stratified Cox model using the same stratification values as for the log-rank test (Cox 1972).  
Median OS in the control arm is expected to be 11 months from randomization, with 120 
deaths needed to provide 90% power to detect a reduction in the OS hazard ratio to 0.55 (i.e., 
median OS of 20 months in the experimental arm) using a two-sided Type I error rate of 0.05 
and accounting for an interim analysis after 84 events. 
Approximately 220 subjects will be randomized at a 1:1 ratio.  
Safety evaluations will be done on all randomized subjects who receive at least one dose of 
GC4711 or placebo.  Acute and late adverse events (CTCAE v5) will be summarized by 
treatment arm.  A Data Monitoring Committee (DMC) will perform an analysis after 
approximately 20 subjects are enrolled and have reached the 4-week post-SBRT timepoint and 
will periodically review safety data and related delays in SBRT administration throughout the 
whole study as outlined in the DMC Charter. 
In addition to an interim test of superiority planned at N=84 deaths (70% information) as 
detailed below, a preliminary assessment will be performed at approximately N=36 events 
(30% information) to assess treatment effect and potentially result in decision to stop the trial 
early. 
An interim analysis of the OS primary endpoint is planned after approximately 84 events 
(deaths) have occurred with controlled disclosure of the results to maintain blinding for the 
full study.  Additional details will be provided in the Statistical Analysis Plan (SAP).  
Secondary efficacy end points (time-to-event endpoints PFS, LCR, and TDM; and overall and 
in-field best response rates) will be measured on CT imaging following RECIST 1.1 and 
centrally reviewed.  Kaplan-Meier estimates of time-to event endpoints will be made.   
Because surgical resection has been reported as associated with improved OS and PFS for this 
patient population (Mellon 2015, Jaoude 2020), the rate of surgical resection will be 


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documented and compared between treatment arms.  Surgical exploration rates, margin status 
(R0, R1) and pathologic response will be summarized and compared descriptively.   
Exploratory endpoints will be summarized and analyzed descriptively and include CA19-9 
normalization (≤ 37 U/ml) and a decrease of ≥ 30% (van Veldhuisen 2018), BRCA mutation 
impact, and changes in patient reported symptoms (PRO-CTCAE), 
 
 


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Figure 1: Study Design 
Screening & response evaluation 
≥ 6 weeks chemotherapy 
Randomization 
optional 
chemo 
SBRT planning & optional additional 
chemo 
Response evaluation 
optional 
chemo 
Pancreatic 
Cancer 
Inoperable 
borderline 
resectable or 
unresectable
/medically 
inoperable 
  
  
5 days  
SBRT + placebo 
5 days  
SBRT + 
GC4711  
Surgical 
exploration 
Follow-up:  
 
every 3 months 
through 22 months 
  
Every 6 months 
through 34 months  
 
Final Survival 
assessment at  
36 months 
Identification & Screening 
Randomization & Treatment 
Follow-up 


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Table 1: Schedule of Assessments 
  
SCREENINGa 
RANDOMIZATIONb 
OPTIONAL CHEMOTHERAPY P 
ACTIVE TREATMENT PERIOD 
 
 
SBRT Visits 
(5-10 days) 
M1(4 weeks  post-
SBRT) 
M3r 
M4, 7, 10, 
13, 16, 19, 
22 
M28, 34  
 
 
 
M36 
 
(day -28 to 1) 
1 
2 
3 
4 
5 
± 15 days 
+ 7 days 
+14days 
+14 days 
 
Informed consent 
X 
 
 
 
Inclusion and exclusion criteriab 
X 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Complete physical examination including 
weight 
X 
 
 
 
 
 
X 
 
Xs 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
X 
X 
Xs 
 
 
Vital signsd 
X 
X (before and after study infusion) d 
X 
 
 
 
 
12-lead ECGe 
X 
X 
X 
 
X 
X 
 
 
 
 
 
AE/SAE reviewf 
 
X 
X 
X  
X 
 
 
Concomitant medication, treatment, and 
supportive care review g 
X 
X 
X 
X  
X 
X 
X 
Survival statush 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Serum pregnancy test (WOCBP) 
X n 
Xn 
 
 
 
 
 
 
 
 
 
Serum chemistry panel 
X 
 
 
 
 
 
X 
 
 
 
 
Complete blood count with differential 
X 
 
 
 
 
 
X 
 
 
 
 
CT chest/abdomen 
X 
 
 
 
 
 
Xq 
 
X 
X 
 
MRI (abdomen) 
X o 
 
 
 
 
 
X  
 
 
 
 
PRO-CTCAE questionnaire 
X 
 
 
 
 
X 
X 
 
X (M7,13) 
 
 
GC4711 or placebo IV infusion 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SBRT administrationi 
  
X  
X  
X  
X  
X  
  
  
 
 
 
Blood samples for PK analysisj 
  
X  
X  
  
X  
X  
  
  
 
 
 
Endoscopy + biopsyk 
X  
  
  
  
  
  
  
 
 
 
CA19.9 l 
X  
  
  
  
  
  
X  
X   
X l 
 
 
Multi-disciplinary review summary sheetm 
X 
 
 
 
 
 
 
X 
 
 
 
 


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AE = adverse event, BP = blood pressure, CT = computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, ECG = electrocardiogram, ECOG = Eastern 
Cooperative Oncology Group, EOS=End of Study, FU = Follow-up, IV = intravenous, M = month, MRI = magnetic resonance imaging, PE = physical examination, PK = 
pharmacokinetics, SAE = serious adverse event, WOCBP= women of childbearing potential  
a A previously performed CT scan, MRI scan, safety blood work (serum chemistry and complete blood work) or other study assessments done per standard of care 
may be utilized for screening if done within 28 days prior to randomization. 
b Randomization should occur after all screening assessments are performed, eligibility is confirmed, and within 5 weeks before the first dose of SBRT. 
Confirmation of eligibility should include confirmation of diagnosis and histology and exclusion of distant disease by standard practice. Reason for inclusion of 
resectable subjects who refuse surgery will be clearly documented (performance, co-morbidity, decline, other). 
c If BRCA mutation is tested/known, it should be documented in source and CRF. 
d Blood pressure and heart rate should be taken prior to each infusion, monitoring possible hypotensive symptoms, and repeated at the end of infusion.  
e Triplicate ECGs should be collected pre- and post-infusion as close to blood draws for PK analysis as possible. The end of infusion PK blood sample should be 
drawn within 10 minutes after the end of the infusion, and the ECG should be performed within 10 minutes of the blood draw for PK analysis. Only a single ECG 
is required at screening and at the 24-hour post dose assessment.   
f All AEs/SAEs will be collected for all randomized subjects who receive at least one dose of study drug starting from the Day 1 dosing through 90 days post-SBRT, 
regardless of disease status. Ongoing SAEs at 90 Days post-SBRT will be followed through resolution. After 90 days post-SBRT, AEs/SAEs associated with late 
toxicities will be followed through 1-year post-SBRT or until distant disease progression, whichever comes first. 
g Medications taken from 30 days prior to dosing through 3 Months post SBRT should be documented in source records and CRF.  After the 3 Month follow up 
visit, only medications used to treat late radiation toxicities should be recorded through 1 year (or distant disease progression, whichever comes first), including 
inhalers, steroids, oxygen supply, etc.  Additionally, any new anti-cancer therapy given at any point during follow-up (including survival follow-up) should be 
recorded in the CRF through 36 months post-SBRT. 
h If a subject experiences distant disease progression, survival status will be followed every 3 months through 2 years post-SBRT and then every 6 months until 3 
years. Telephone contacts are acceptable for survival follow up. No additional study assessments or AE/SAE recordings will be required after documented distant 
disease progression, following 90 days post SBRT completion. 
i SBRT will start from 7 to 42 days after the last pre-SBRT chemotherapy cycle (the 7 – 42-day window will begin at the end of the treatment cycle, not on the last 
day of actual treatment time) and will start within 5 weeks from randomization. SBRT will be administered in 5 daily doses (minimum of 18 and maximum of 72 
hours between fractions. Additionally, an occasional 96-hour window is acceptable (i.e. in case of a holiday or machine breakdown).  GC4711 or placebo will be 
administered prior to each dose of SBRT starting on the first day of SBRT through the last day of SBRT. GC4711 or placebo will be administered within 180 
minutes prior to the start of SBRT. 
j Blood samples for PK analyses should be taken at Day 1 of GC4711 or placebo infusion (before, immediately after, and 24 hours after the Day 1 infusion but 
before next study drug infusion and on Day 4 of GC4711 or placebo infusion (before, immediately after, and 24 hours after the Day 4 infusion but before infusion 
on Day 5).  
k A previous endoscopy and biopsy performed prior to screening may be utilized for confirmation of diagnosis. If BRCA mutation was tested, this should be 
documented. In case of suspicion of macroscopic tumor in the bowel lumen, a repeat endoscopy evaluation prior to SBRT is recommended and can be combined 
with fiducial positioning if used for CT-guided patient set-up. A repetition of the biopsy is not needed, if a repeat endoscopy is done. 
l Local lab values and normal range of CA19.9 should be collected at screening as close to randomization as feasible and at each follow-up visit for the first year or 
until documented local or distant progression. CA19.9 value at time of diagnosis and disease progression should be documented, if available.  
m Multi-disciplinary judgement on technically and medically resectability, as well as SBRT feasibility are documented.  


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n A serum pregnancy test must be performed within the screening period.  A urine pregnancy test must be performed on Day 1 prior to dosing and prior to 
chemotherapy restart following SBRT. 
o An MRI of the abdomen is required to be done prior to SBRT for adequate planning and may be completed following randomization and as close to SBRT as 
feasible.  When MRI is contraindicated, a CT is acceptable if fiducials have been placed. 
p Subject may be given additional chemotherapy following randomization prior to SBRT start but it is not required. SBRT must start from 7 to 42 days after the last 
pre-SBRT chemotherapy cycle (the 7 – 42 day window will begin at the end of the treatment cycle, not on the last day of actual treatment time).    
q CT-based observed local disease progression at 4-weeks post SBRT requires confirmation at the next scheduled imaging timepoint. Subjects with local (regional) 
progression without distant disease will be continued in follow-up (visits, CT scans) as by Schedule of Assessments (SOA). After documented distant disease 
progression, no further protocol assessments are required and follow up will change to survival only with the collection of additional anti-cancer therapy given. 
r The month 3 visit may be done by telephone if subject is unable to visit the site. CA19.9 can be collected locally.  
s Physical Exam and ECOG should be completed every 3 months through 13 months.  
 
 
Figure 2: Subject Flow 
Subject 
starts 
chemo 
CT Scan  
SBRT planning 
≤ 28 days 
 ≥ 6 
weeks 
Patient 
signs 
consent 
≤ 28 
days 
Randomize 
subject 
≤ 5 
Weeks 
Day 1 SBRT 
+ study 
drug 
≤ 10 
days 
Day 5 
SBRT + 
study 
Patient finishes last  
chemo cycle 
7-42 days 
2-6 
Weeks 
1 
month 
FU 
Long 
Term FU
Surgical Exploration, if 
possible 
≤ 8 weeks 


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2 INTRODUCTION 
2.1 Radiotherapy for Unresectable or Borderline Resectable Pancreatic Cancer 
Pancreatic cancer (PC) is a one of the most lethal cancer diagnoses today. Incidence is rising, and 
the estimated 5-year survival rate is only 9% (Rawlaa 2019, Ryan 2014). At the time of diagnosis, 
approximately half of patients present with metastatic disease (stage IV), and less than 10% present 
with resectable disease. All other patients are classified unresectable or borderline resectable 
(NCCN v.1.2020, Appendix 5) as determined by the extent of tumor contact with the vascular 
system, limiting resection as well as radiotherapy (RT) because of proximity to the bowel structures 
(Murphy 2018, Palta 2019).  
 
The American Society of Clinical Oncology and NCCN v1.2020 (Appendix 5) defined more exact 
criteria for borderline resectable and unresectable PC using computed tomography (CT) and 
magnetic resonance imaging (MRI) and recommended induction chemotherapy followed by local 
therapies such as (chemo) radiotherapy (RT) and/or surgery (Palta 2019, Khorana 2019, 
Balaban 2016) for patients responding to 3 or more cycles of induction chemotherapy. Selecting 
responding patients is important for avoiding toxicities and the costs associated with local treatment 
in patients with fast progressing distant disease. In borderline and unresectable patients judged 
‘technically resectable’ (Al-Hawary 2014, NCCN v1.2020, Appendix 5), surgical exploration is 
recommended within 8 weeks after RT, where possible, yielding an important impact on survival 
(Mellon 2015, Jaoude 2020).  
 
While systemic treatment of PC has improved, patients with borderline or unresectable PC 
nevertheless still have low resection rates and poor outcomes overall. Both toxicity and disease 
progression during induction chemotherapy limit the number of potential candidates for surgery 
(Maggino 2019, Lambert 2019). NCCN guidelines state (m)FOLFIRINOX (Von Hoff 2013, Suker 
2016) or Gemcitabine-doublet (Conroy 2011) as first choice of neoadjuvant treatment, extrapolating 
from series in adjuvant and metastatic settings. Both regimens have proven benefit over 
gemcitabine-only, however, differ in toxicity profile (Perri 2020, Chiorean 2019, Pusceddu 2019, 
Cho 2020). Alterations in germline BRCA and PALB2 are detected in approximately 5–9% of 
patients with PC and can lead to homologous repair deficiency (HRD). PC with HRD is more 
susceptible to cytotoxic agents, such as platinum salts and topoisomerase inhibitors, favoring first-
line gemcitabine-cisplatin chemotherapy (Wong 2020). BRCA carriers are often prescribed 
gemcitabine-cisplatin, however, increased rate of pathological response after neoadjuvant 
FOLFIRINOX (Golan 2020) is reported. Systematic testing of mutations is, however, not in current 
standard of care guidelines (NCCN.org).  
In the protocol, FOLFIRINOX, (m)FOLFIRINOX or gemcitabine-doublet are inclusion criteria, 
while allowing simplification and dose-reduction for toxicity (expected in up to half of subjects 
over 6 months, Suker 2016). Switching of the treatment regimen is permissible per institutional 
practice/SOC/NCCN guidelines.  
Optimal use of local treatment, including stereotactic body radiation therapy (SBRT), is evolving 
(Balaban 2016, Palta 2019). Neoadjuvant radiation at moderate dose has been reported to improve 


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local control but not overall survival (OS) (Krishnan 2016, Hammel 2013, Polistina 2010, 
Chin 2018); thus, RT has been shifting to higher dose delivery (Schellenberg 2011, Colbert 2018, 
Petrelli 2017) with the goal of improving surgical intervention rates and overall outcomes 
(Mellon 2015, Jung 2019). Use of SBRT regimens that employ 3-5 fractions have been reported to 
show acceptable toxicity profiles (Sutera 2017, Shaib 2016, Reyngold 2019, Palta 2019, 
Suker 2019, Boldrini 2019, Mellon 2015, Herman 2015) and superiority to conventionally 
fractionated RT (Zhong 2017, Petrelli 2017). Online imaging has made SBRT even more precise 
and a 5 ×10 Gy regimen is regarded as safe (Hassanzadeh 2020, Henke 2018). Tumor control with 
SBRT still offers ample opportunity for improvement, however, and normal tissue constraints limit 
tumor coverage and present a toxicity risk (Elhammali 2015, Reyngold 2019, Jung 2019).  
2.2 Investigational Medicinal Product  
GC4711 is a novel, water-soluble, low-molecular weight, manganese pentaaza-macrocyclic ligand 
complex (MnPAM) whose catalytic activity for the dismutation of superoxide to hydrogen peroxide 
mimics that of naturally occurring superoxide dismutase (SOD) enzymes. GC4711 and other 
MnPAMs are a new pharmacologic class of drugs, which are termed selective dismutase mimetics, 
that are being developed for administration by intravenous (IV) infusion.  
SOD enzymes are expressed in the cytoplasm (SOD1 Cu/Zn-based), mitochondria (SOD2, Mn-
based), and extracellular spaces (SOD3, Cu/Zn-based) of mammalian cells (Fridovich 1997). These 
enzymes eliminate superoxide (O2•-) by converting it to hydrogen peroxide (H2O2), which is then 
further detoxified by peroxidase enzymes producing molecular oxygen (O2) and water (H2O) 
(Fukai 2011, Miller 2012). In certain inflammatory disease states and during RT and chemotherapy 
for cancer, native SOD enzyme activity can be overwhelmed due to excessive superoxide 
production, resulting in normal tissue damage (Mapuskar 2019). Thus, the removal of excess 
superoxide with supraphysiological levels of SOD activity can protect normal tissues from 
therapeutic radiation damage, as has been demonstrated by multiple lines of evidence (Thompson 
2010, Greenberger 2007, Murphy 2008, Anderson 2018, 2019).  
GC4711 and its MnPAM analogues are highly selective and specific dismutase mimetics. Studies 
with the GC4711 analogue, GC4419, employed electron paramagnetic resonance to demonstrate 
that it quenched the increased levels of O2•− formed in cancer and normal cells but did not alter the 
hydroxyl radical (OH) generation by radiation that is believed primarily responsible for cancer cell 
DNA damage and killing (El-Mahdy 2020). Consistent with this, combining GC4419 with radiation 
augmented the cytotoxic effects of radiation on cancer cells while protecting normal cells.  
In vivo, mouse tumor model studies with GC4711 and analogues in combination with high dose per 
fraction radiation have shown anti-cancer synergy (Sishc 2018). In other animal models, GC4419 
has shown reduction of normal tissue radiation toxicity (El-Mahdy 2020, Sishc 2019), and another 
analogue, GC4403, demonstrated radioprotection of the small intestine (Thompson 2010) and oral 
epithelium (Murphy 2008). Similarly, in a randomized, double-blind, placebo-controlled Phase 2b 
trial, GC4419 demonstrated a reduction in the incidence and severity of oral mucositis due to RT for 
head and neck malignancies (Anderson 2018, 2019).  
MnPAM dismutase mimetics demonstrate mechanism-related anti-tumor synergy with high dose 
per fraction radiation. 


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SBRT greatly increases cellular superoxide concentrations, which selective dismutase mimetics 
exploit to generate high levels of hydrogen peroxide, creating a highly toxic environment for tumor 
cells, as hydrogen peroxide is more toxic to tumor cells than to normal cells. This cancer cell 
sensitivity may reflect lower levels of catalase, glutathione peroxidase, and other enzymes that 
degrade hydrogen peroxide in the cancer cell (Oberley 1997), a translocation of catalase 
(Bohm 2015), or susceptibility of cancer metabolism. As superoxide levels and thus the amount of 
hydrogen peroxide produced by the selective dismutase mimetic increase with fraction dose size, 
hydrogen peroxide levels can reach levels that have significant anti-tumor effects 
(Greenberger 2007, Sishc 2021, Sishc 2019). In a model in which the H1299 tumor was engineered 
to express catalase inducible with a doxycycline promoter, these synergistic anti-tumor effects were 
demonstrated to be related to the mechanism of the dismutase mimetic GC4419 (Sishc 2021). 
GC4711 alone, administered once daily at 24 mg/kg for 5 consecutive days, significantly delayed 
growth of H1299 NSCLC lung or Panc 02.03 pancreatic tumors in xenografted mice compared with 
vehicle control animals ( 
 NSCLC and Error! Reference source not found. for PC). The combination treatment of 24 mg/kg 
GC4711 administered on Days 1 to 5 and 18 Gy in lung and 12Gy in PC SBRT on Day 1 
demonstrated an additive effect on tumor growth, resulting in smaller average tumor volumes 
compared with GC4711 or SBRT alone. 
 
Figure 3: GC4711 Potentiated the Antitumor Effects of SBRT in a Human NSCLC Model 
 
NSCLC = non-small cell lung cancer; SBRT = stereotactic body radiotherapy. 
H1299 cells (ATCC® CRL-2553™) were implanted by subcutaneous (SC) injection into the flank of 6-week-old female nu/nu mice. 
When the average tumor size per group reached 100 mm3, treatments were initiated. A single SBRT dose (18 Gy) was administered 
once on Day 1. Control and GC4711 groups (n = 9-12 animals per group) received the vehicle (10 mM sodium bicarbonate in saline) 
or 24 mg/kg GC4711 in vehicle by intraperitoneal (IP) injections approximately 30 minutes before the 18 Gy SBRT dose and on 
Days 2 through 5. Tumor dimensions were measured 2 times per week by caliper and tumor volumes calculated. Tumor volumes 
expressed as the group mean +/- standard error of the mean. 
  


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Figure 4: GC4711 Potentiated the Antitumor Effects of SBRT in a Human Pancreatic 
Adenocarcinoma Model 
 
SBRT = stereotactic body radiotherapy. 
The human pancreatic adenocarcinoma cell line, Panc 02.03 (ATCC® CRL-2553™), was implanted by subcutaneous (SC) injection 
into the flank of 6-week-old female nu/nu mice. When the average tumor size per group reached 100 mm3, a single 12 Gy dose of 
SBRT was administered (Day 1). Control and GC4711 groups (n = 9-12 animals per group) received the vehicle (10 mM sodium 
bicarbonate in saline) or 24 mg/kg GC4711 by IP injection approximately 30 minutes before SBRT and on Days 2 through 5 
(consecutive days). Tumor dimensions were measured 2 times per week by caliper and tumor volumes calculated. Tumor volumes 
expressed as the group mean +/- standard error of the mean. 
 
2.3 Pilot clinical data with GC4711 analogue GC4419  
A pilot, randomized, double-blinded, placebo-controlled multicenter adaptive dose-finding trial of 
SBRT with the GC4711 analogue GC4419 (GTI-4419-101) was conducted in patients with locally 
advanced PC. After completing first-line chemotherapy, 42 patients with unresectable (32 subjects) 
or borderline resectable (10 subjects) PC were randomized in a double-blind fashion to receive 
either 90 mg GC4419 or placebo (PBO) via IV infusion prior to each of 5 daily SBRT fractions 
(planned 5 ×10, 11, or 12 Gy). Median duration of chemotherapy prior to randomization was 22 
weeks (range, 12-36) for placebo and 18 weeks (range, 9-67) for GC4419.  SBRT dose assignment 
started at 10 Gy per fraction and proceeded separately in each arm based on dual endpoints (Gr 3-4 
GI toxicity/death through 90 days post SBRT, and local stable disease/improvement at 90 days post 
SBRT) using a Late Onset Efficacy/Toxicity tradeoff (LO-ET) Bayesian adaptive design in which 
acceptable posterior probabilities of 90-day safety and efficacy were set at 0.15 and 0.75, 
respectively. The primary endpoint was recommended SBRT dose for further study in each arm, 
based on the LO-ET model.   Other endpoints included acute (90 day) and late (12 month) radiation 
toxicity, OS, progression-free survival (PFS), locoregional control (LRC), and time to distant 
metastases (TDM). 
All subjects completed the assigned SBRT: 5 × 10 Gy (n=24) or 5 × 11 Gy (n=18).  The design 
called for 24 subjects per arm in a 1:1 randomization, but the placebo arm was terminated early, 
prior to the maximum sample size of 24 patients, at 18 patients, due to unacceptably low probability 
of efficacy at any dose, compared to the fixed lower limit of 0.75. 


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An SBRT dose regimen of 10 Gy x 5 was selected for further study in the present trial. 
Final analysis of safety and efficacy is available after completion of 12-month follow up for all 
surviving patients (data on file, Galera Therapeutics, Inc).  The adverse event profiles for GC4419 
and placebo were similar (Table 2a2a and Table 2b).  Hazard ratios of <0.5 for OS, PFS, local 
control, and time to distant metastases (Table 33) suggested an efficacy benefit for the dismutase 
mimetic, supporting further study with GC4711 in the present trial. 
Table 2a: Safety summary from pilot randomized trial GTI-4419-101 
AEs Considered related by 
Investigator to SBRT 
SBRT + PBO 
SBRT + GC 
≤90 days after 
SBRT 
Any AE 
67% 
46% 
GI AE 
44% 
42% 
Severe AE 
0% 
0% 
>90 days after 
SBRT 
Any AE 
22% 
25% 
GI AE 
17% 
21% 
Severe AE 
11% 
8% 
 
Table 2b:  Safety summary from pilot randomized trial GTI-4419-101 
AEs Considered related by Investigator to 
GC/PBO 
SBRT 
+ PBO 
SBRT 
+ GC 
≤90 days after SBRT 
Any AE 
67% 
46% 
GI AE 
44% 
42% 
Severe AE 
0% 
0% 
>90 days after SBRT 
Any AE 
17% 
21% 
GI AE 
17% 
17% 
Severe AE 
11% 
4% 
 
Table 3: Comparison of tumor outcomes after SBRT with GC4419 or placebo in the pilot trial 
GTI-4419-101   
Arm 
Median (Months) 
 
OS  
PFS 
LRC 
TDM 
GC4419 (n=24) 
17.0 
11.2 
24.2 
13.9 


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PBO (n=18) 
13.3 
7.1 
9.6 
7.0 
Hazard Ratio 
0.48 
0.46 
0.30 
0.39 
P (log-rank) 
0.09 
0.04 
0.06 
0.03 
Abbreviations: NR = not reached 
Source: Galera Therapeutics, Inc, data on file 
 
2.4 GC4711 Nonclinical Safety Data 
Four GLP 14-day repeat-dose studies with 14-day non-treatment recovery periods were conducted 
in Sprague-Dawley rats and beagle dogs using either 15- or 60-minute GC4711 IV infusions.  
Key safety findings in the GLP toxicity studies were as follows:  
• GC4711 was overall well tolerated in rats and beagle dogs in all repeat-dose studies 
with no adverse effects on central nervous system or respiratory parameters in rats 
(15-minute infusion) and no adverse cardiovascular effects in dogs (15-minute 
infusion). 
• Mortality was observed in 2 rats in the 15-minute infusion study at the high dose 
level of 16 mg/kg/day, and these deaths were of unknown relationship to GC4711. 
• Adverse effects included weight loss, which was observed in rats at doses of 16 
mg/kg/day (15-minute infusion) and 18 and 24 mg/kg/day (60-minute infusion). The 
rat AEs were reversible during the 14-day recovery period.  
• The no observed adverse effect level (NOAEL) was 8 mg/kg/day for rats and 9 
mg/kg/day for dogs in the 15-minute GC4711 infusion studies. The NOAEL was 12 
mg/kg/day for rats and 12.5 mg/kg/day for dogs in the 60-minute GC4711 infusion 
studies. 
• There were no indications of clastogenicity or genotoxicity associated with 
administration of GC4711.  
For additional information, please refer to the GC4711 Investigator’s Brochure (IB). 
2.5 GC4711 Clinical Development  
The clinical development of GC4711 comprises three clinical studies. Initially, the safety and 
plasma exposure of healthy volunteers to GC4711 was compared to that of the analogue, GC4419, 
which is in development for reduction of RT-induced oral mucositis (Study GTI-4711-001). Based 
on their structural similarities, it was hypothesized that, at equimolar doses administered by the 
same route and schedule, the safety and plasma exposure of GC4711 and GC4419 in human 
subjects would be similar, and results of GTI-4711-001 supported this hypothesis, facilitating 
further work to identify GC4711 doses of interest for clinical study considering prior experience 
with GC4419. Additional information regarding the safety and pharmacokinetic results of this 
completed study are available in the IB. 
In addition, safety data with GC4711 have been obtained at a dose of 30 mg by 60-minute IV 
infusion in an ongoing study (Study GTO-003) in which the bioavailability of various candidate 
oral formulations of GC4711 is being assessed to identify a suitable formulation for future clinical 
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A Phase 1 Study (Study GTI-4711-002) involving serial cohorts of healthy volunteers who received 
GC4711 or placebo via 15-minute IV infusion at a single dose up to 120 mg of GC4711 (Cohorts 1-
6: 30, 60, 75, 90, 105, or 120 mg) and then via once daily 90 mg infusions for 14 days (Cohort 7) 
has been completed. A total of 10 subjects in each cohort were randomized at a 6:4 ratio to receive 
GC4711 or placebo treatment. All cohorts included a sentinel cohort consisting of 2 subjects (1 
GC4711, 1 placebo) who were observed for at least 24 hours following infusion and the safety data 
were reviewed by the treating investigator before dosing the rest of the subjects in the cohort.  
In this study, the pharmacokinetics (PK) profile of GC4711 following 15-minute IV infusion at 
doses from 30 mg to 120 mg as a single dose and 90 mg/day for 14 days revealed the following 
results:  
• Quantifiable plasma concentrations for up to 6 to 12 hours after infusion were observed 
across all dose cohorts. 
• Greater than dose proportional behavior for the concentration maximum (Cmax) and area 
under the curve (AUC) of GC4711 across single dose administration cohorts. For GC4711, 
this behavior may be attributed to the fact that the first dose (30 mg) was not measurable for 
a long period of time, resulting in a much lower AUC. 
• The half-life (t1/2) for GC4711 was approximately 2 hours. 
• Low levels of exposure to the GC4711 metabolites GC4764 and GC4765, with metabolite to 
parent ratios of < 6% and 1.2%, respectively, across all dose cohorts. Based on the 
combination of low prevalence and biological activity in nonclinical studies, these 
metabolites do not appear to be of clinical significance in human patients. 
• No marked accumulation of GC4711 was observed by Day 8 following daily administration 
of 90 mg/day. 
The safety profile of GC4711 was comparable following single 15-minute IV infusion doses up to 
120 mg and multiple 15-minute IV infusion doses of 90 mg/day for 14 days. Consistent with the 
mechanism of action of GC4711 (specifically, potentiation of nitric oxide (Kasten 1994)), transient 
orthostatic symptoms (e.g., headache, dizziness, and light-headedness), hypotension, and facial 
tingling or paresthesia were expected and consistently observed. Reports of paresthesia appeared to 
be dose-related; however, it was mild to moderate in intensity and was not treatment-limiting. All 
treatment-emergent adverse events (TEAEs) were Grade 1 or Grade 2 in intensity. None of the 
TEAEs were graded serious, and there were no deaths. No clinically significant abnormalities in 
any laboratory evaluations were noted. Please see the IB for further details.  
Assessment of ECG data from the single ascending dose cohort of the Phase 1 study (Study GTI-
4711-002) demonstrated no clear dose-related trends, nor changes in ECG measures or shifts from 
normal to abnormal that were clinically significant. Overall, there were 3 subjects (1 [16.7%] at 30 
mg and 2 [33.3%] at 120 mg) who reported ECG changes that were judged to be not clinically 
significant. This addressed shifts in QT interval 2 hours after the infusion relative to baseline (5.3 
msec for the subject in the 30 mg group and +5.0 and +16.7 msec for the subjects in the 120 mg 
group) and QTcF interval (5.3 msec for the subject in the 30 mg group and +9.0 and +7.7 msec for 
the subjects in the 120 mg group). Although these ECG shifts were rated as not clinically 
significant, ECG and QT intervals are to be closely followed when patients are first exposed to 
GC4711 (Section 8.3). 


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Overall, the safety profile of GC4711 from healthy volunteer populations is acceptable to further 
investigate safety testing in PC patients.  
2.6  Rationale for Present Trial 
Mechanism and nonclinical data with the MnPAM dismutase mimetics strongly suggest anti-tumor 
synergy with high dose per fraction radiation (SBRT) and protection of normal tissue from 
radiation-related injury. With respect to the proposed indication here, GC4711 has demonstrated 
anti-tumor synergy in combination with SBRT (12 Gy x 1) in a pre-clinical xenograft model of 
pancreatic cancer (Sishc 2020, Thompson 2010, Error! Reference source not found.). Interim 
results of the pilot clinical trial (GTI-4419-101) of GC4419 (an analogue of GC4711) plus SBRT in 
locally advanced PC further support this class anti-tumor synergy and the safety of a 5 × 10 Gy 
SBRT regimen in this population.   
The safety of GC4711 has been established in healthy subjects following administration via 15-
minute and 60-minute IV infusions. There were no unexpected safety findings, and the overall 
safety profile of GC4711 was comparable following single 15-minute IV infusion doses up to 120 
mg and multiple 15-minute IV infusion doses of 90 mg/day for 14 days. Further, a crossover study 
in healthy human subjects demonstrated similar safety and plasma exposure to the MnPAM 
dismutase mimetic analogues GC4711 and GC4419 administered via IV infusion at approximately 
equimolar doses. A 100 mg dose of GC4711 is approximately equimolar to the 90 mg dose of 
GC4419 used in the pilot SBRT combination trial in patients with PC and in the IMRT combination 
oral mucositis clinical trials in head and neck cancer. 
Therefore, based on nonclinical pharmacology studies and previously collected clinical data, 
GC4711 is an appropriate experimental drug candidate to study its potential to safely provide 
significant benefit to PC patients by improving tumor response to SBRT without increasing the risk 
of GI toxicities. By the virtue of being a short one-week regimen, SBRT can be given earlier in the 
clinical pathway before chemotherapy resistance (including early metastasis) or unacceptable 
toxicity may develop (Suker 2016, Lambert 2019).  
3 OBJECTIVES AND ENDPOINTS 
3.1 Rationale for Primary Endpoint 
OS is a critical endpoint for analysis of treatment efficacy in non-metastatic PC. In literature 
(Mellon 2015, Jaoued 2018) both OS and PFS are largely dependent on local response enabling 
resection of the primary tumor, being the driver in survival outcome. Chemotherapy can control 
distant disease, but local disease control requires this surgical intervention. The potential for 
surgical intervention is improved with each effective treatment modality, including SBRT, which is 
known to increase surgical candidates and positively impact daily life, leading to survival benefit in 
PC patients (Herman 2015, Bonnetain 2014, Kovic 2018, Hamada 2016).  
 
 


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OBJECTIVES 
ENDPOINTS 
Primary 
To determine the effect on OS of adding 
GC4711 to SBRT compared to placebo in 
subjects with unresectable or borderline 
resectable, nonmetastatic PC 
Overall Survival Status followed for 3 years post 
SBRT 
Secondary 
• To evaluate the effects of adding 
GC4711 to SBRT on progression-free 
survival (PFS) locoregional control 
(LRC), and time to distant metastases 
(TDM) 
• To evaluate the overall and in-field 
response following GC4711 + SBRT 
• To evaluate surgical resection 
outcomes: proportion of subjects in 
whom R0 or R1 resection is achieved; 
pathological response in resected 
specimens  
• To evaluate the acute and late toxicity 
observed after SBRT 
 
For PFS, LRC, TDM, Best Overall and in-field response:  
• CT (chest/abdomen) using RECIST 1.1 
(Appendix 2) 
For resection rates: 
• Multi-disciplinary review of resectability 
judgements and in explored subjects, margin (e.g., 
R0/R1) and pathological response (pCR, pNR, 
pPR, no response) status will be recorded.  
• For toxicity/safety: Reporting all observed 
AEs/SAEs in first 90 days by NCI-CTCAE, 
version 5.0 (See Section 8.4 and Appendix 4) and 
specific late toxicities until distant disease 
progression or 1 year (See Section 6.4, Table 3, 
including bowel stenosis, obstruction or 
perforation, abdominal bleeding, vascular events, 
kidney or liver failure, and spinal cord injuries). 
Exploratory  
• To evaluate the effect of GC4711 + 
SBRT on patient-reported symptoms  
• To evaluate changes in CA19-9 with 
GC4711 + SBRT 
• To assess pharmacokinetics of 
GC4711 in the study population  
 
• PRO-CTCAE pancreas to evaluate patient-
reported symptoms (Basch 2014, 
Kluetz 2016,Appendix 6) 
• CA19.9 values will be documented at diagnosis, 
screening and after SBRT at all visits during the 
first year or until distant or local disease 
progression. 
• Plasma concentrations of GC4711 and major 
metabolites 
 


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4 STUDY DESIGN 
4.1 Overall Design 
GTI-4711-201 is designed to determine the effect on OS of adding GC4711 to SBRT after 
chemotherapy in subjects with unresectable or borderline resectable, nonmetastatic PC. This is a 
Phase 2b, multicenter, randomized, double-blind, placebo-controlled study, wherein approximately 
220 subjects will be randomized.  
Patients will be randomly assigned, in 1:1 ratio, to study either GC4711 or placebo for an estimated 
110 patients per arm. Patients will be randomized at approximately 25 centers in the US, and 15 
additional centers outside the US (Canada, EU, or UK). See Section 9.1 for Sample Size 
Determination. 
Subjects must be diagnosed with nonmetastatic unresectable or borderline resectable PC or be 
medically unfit for surgery for PC. Subjects who remain metastasis-free after response evaluation 
following chemotherapy will be considered for participation. Eligible subjects will be randomized 
in a 1:1 ratio to receive either GC4711 100 mg (Arm A) or placebo (Arm B) via IV infusion over 15 
minutes (+5 min) before each of 5 fractions of SBRT, beginning the day of the first fraction of 
SBRT and ending the last day of SBRT (Figure 1: Study Design). 
All newly diagnosed subjects will receive at least 6 weeks of chemotherapy consisting of EITHER 
a) FOLFIRINOX, modified FOLFIRINOX (without bolus administration 5FU, q14) OR b) a 
gemcitabine-doublet regimen (e.g., gemcitabine combined with nab-paclitaxel, cisplatin, 
capecitabine, q30) prior to SBRT. There is no upper limit on the number of pre-SBRT 
chemotherapy cycles that a subject may receive as long as there is no evidence of metastatic spread 
during treatment with the initial chemotherapy regimen.  Subjects may change chemotherapy 
regimens prior to SBRT (but still limited to FOLFIRINOX, mFOLFIRINOX or a gemcitabine-
doublet regimen) for issues of toxicity or intolerance, per institutional practice/SOC/NCCN 
guidelines. Subjects with local progression are not excluded as long as they remain non-metastatic 
at screening Subjects who commence chemotherapy with single-agent gemcitabine but who are then 
able to tolerate either a gemcitabine doublet, FOLFIRINOX or mFOLFIRINOX may also be 
included in the trial as long as they fulfill the requirements for at least 6 weeks of pre-SBRT 
combination chemotherapy with these regimens as outlined above. Other variations such as 
FOLFOX or FOLFIRI are also acceptable; any other variations must be discussed with the Medical 
Monitor prior to randomization. After at least 6 weeks of combination chemotherapy subjects will 
be evaluated by CT and MRI scan for SBRT feasibility and for disease progression; those without 
metastases will be considered for enrollment.  
Eligible subjects will be stratified at randomization based on disease status at diagnosis: borderline 
resectable vs unresectable (radiographically or medically inoperable, as determined by the 
multidisciplinary group following the NCCN definition v1.2020, see Appendix 5).   
Due to the risk of a radio-sensitizing effect of fluorouracil and gemcitabine, SBRT should not be 
started until at least one week following the end of the last chemotherapy cycle. Following SBRT 
(and surgery, if possible), patients may receive additional adjuvant chemotherapy at the discretion 


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of the investigator per institutional practice/SOC/NCCN guidelines. All anti-cancer therapy will be 
collected and documented through study duration.  
SBRT will be delivered in 5 fractions of 10 Gy to the confirmed residual GTV (macroscopic tumor) 
and at least 30Gy to the CTV, while respecting normal tissue constraints; no nodal elective fields 
will begiven, only macroscopic tumor areas will be targeted (Palta 2019). SBRT fractions should be 
given with MR or CT-image guidance, matching both target and avoidance structures, confirming 
respect of constraints. Fractions will be given within 180 minutes from the end of the GC4711 or 
placebo infusion. Between fractions, a minimum of 18 and a maximum of 72 hours is permitted. 
Additionally, an occasional 96-hour window is acceptable (i.e. in case of a holiday or machine 
breakdown). All 5 fractions must be given within a maximum of 10 calendar days. If a subject is 
unable to receive their treatment within 10 days, the Medical Monitor and Galera study team should 
be notified. Each participating center will provide SBRT certification, and all radiation treatment 
plans will be centrally reviewed. 
Detailed information on the Radiation Therapy Quality Assurance (RTQA), CT/MRI imaging (at 
randomization, RT planning/treatment, and 4 weeks after SBRT) is outlined in the RTQA Manual. 
Blood sampling for PK analysis and cardiac monitoring will be performed on each subject 
following two separate doses of GC4711 or placebo, and samples will be collected pre-infusion, 
immediately after infusion, and 24 hours after infusion for each of the two doses. 
After SBRT, subjects judged by the site’s institutional multidisciplinary group to be technically 
unresectable or medically inoperable or refusing surgery may receive additional chemotherapy at 
the discretion of the investigator, and according to standard of care, institutional practice, and 
NCCN guidelines, as applicable. 
The subjects judged by the multidisciplinary group to be ‘technically and medically resectable’ on 
CT/MRI (Appendix 5) after SBRT will be surgically explored within 8 weeks following SBRT, and 
outcomes of margins and pathology remission will be scored from the local pathology reports.  
Following surgery, additional chemotherapy may be administered at the discretion of the 
investigator and according to standard of care, institutional practice, and NCCN guidelines, as 
applicable. All anti-cancer therapy will be collected and documented through study duration. 
An independent Data Monitoring Committee (DMC) will be established. Refer to Section 9.7. 
All imaging for efficacy assessment will undergo retrospective, independent central review 
(following RECIST 1:1). Local imaging assessments will be used for study eligibility and treatment 
decisions.  
4.2 Study Duration for Participants 
The study duration for participants is expected to be up to approximately 40 months. This includes a 
28-day screening period, chemotherapy, a treatment period with SBRT, surgical exploration where 
possible, additional chemotherapy and follow up for survival, progression and long-term safety. 


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In case of distant disease progression, following the 90-day AE follow up period, subjects will be 
followed every 3 months through 2 years post-SBRT and then at 28, 34 and 36 months post-SBRT 
to monitor survival status and new anti-cancer therapy; no additional study assessments will be 
required after this point. 
4.3 Replacement of Participants 
All subjects randomized will be included in the intent-to-treat (ITT) population. The reasons why 
subjects did not receive SBRT and/or drug will be recorded. Screen-failures (see section 5.2) can be 
replaced if randomization did not take place. 
4.4  End of Study Definitions 
End of Study (Individual Participant): A participant is considered to have completed the study if 
he/she has been followed for survival through death or for at least 3 years following SBRT. 
Primary Completion: The primary completion date is defined as the date when the last participant 
is assessed or receives an intervention for the final collection of data for the primary endpoint for 
the purposes of conducting the primary analysis.  
End of Study (End of Trial): The end of the study is defined as the date of the last visit of the last 
participant in the study. Both the sponsor and the investigator reserve the right to terminate the 
study at any time. In terminating the study, Galera Therapeutics, Inc., and the investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
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 Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)/Research Ethics Board (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. 
4.5  Rationale for SBRT Regimen 
In non-clinical development, GC4711 has shown the potential of increasing efficacy of high-dose 
RT as well as limiting the associated inflammatory and fibrotic reactions in normal tissues. SBRT is 
increasingly used in PC, facilitating dose-escalation; however, dose coverage is still hindered by 
normal tissue constraints. Several reports on multicenter 5-fraction SBRT regimens have confirmed 


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feasibility and potential survival benefits (Suker 2019, Mellon 2015, Herman 2015) as well as 
superiority to conventionally fractionated RT (Zhong 2017). With online imaging tools and adaptive 
planning (CT-on-rails, MR-linac), total dose of 5 × 8 Gy on tumor with 3-mm margins 
(Boldrini 2019, Suker 2019) or 5 ×10 Gy prescribed on tumors with reduced margins towards bowel 
structures (Hassanzadeh 2020, Henke 2018) have been reported safe and are currently being used in 
an on-going clinical trial (NCT03621644). Dose escalation (> 55 Gy) is directly related to survival 
improvement when RT is given after induction chemotherapy, although these doses are limited by 
normal tissue constrains (Jung 2019, Elhammali 2015). 
By adding GC4711 to a 5-fraction SBRT regimen performed with daily image guidance  
(Reyngold 2019, Rudra 2019, Palta 2019), we aim to enhance both tolerance and disease control in 
locally advanced or borderline resectable PC. SBRT will be delivered with BED of 100 Gy in 5 
fractions (Hoyer 2005, Colbert 2018, Petrelli 2017, Jaoude 2020) as used in the GC4419-101 trial 
and the SMART trial (https://clinicaltrials.gov/ct2/show/NCT03621644).  
4.6  Rationale for GC4711 Dose and Schedule  
A GC4711 dose of 100 mg administered via IV over 15 minutes on 5 days concurrent with SBRT 
administered in 5 fractions over the same period is proposed for this trial. In the healthy human 
volunteer study (GTI-4711-002), IV administration of GC4711 was found to be well-tolerated with 
a single administration at dose levels up to 120 mg and with repeated dosing of 90 mg/day for 14 
days or a total weekly dose of 630 mg. Therefore, GC4711 at a dose of 100 mg given daily over 5 
days is expected to be tolerated by cancer patients. 
5 STUDY POPULATION 
Before any study-specific activities/procedures can be performed, the appropriate written informed 
consent must be obtained.  
5.1  Eligibility Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Inclusion Criteria:  
1. 
Histological or biopsy proven adenocarcinoma of the pancreas. Cytology is acceptable if 
histology cannot be obtained 
2. 
Newly diagnosed non-metastatic PC judged by site’s institutional multi-disciplinary 
group to be feasible for SBRT, as well as having measurable disease as defined by 
RECIST 1.1 and classified following NCCN guidelines v1.2020 (see Appendix 5):  
a. Locally advanced and technically unresectable determined by multidisciplinary review 
at the investigative site  
b. Potentially resectable, but subject is judged not a candidate for surgery, determined by 
multidisciplinary review at the investigative site 


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c. Potentially resectable, but the subject refuses surgery and is considered an acceptable 
candidate for SBRT determined by multidisciplinary review at the investigative site 
(reason for b and c are documented at randomization) 
d. “Borderline” resectable, as determined by multidisciplinary review, including absence 
of distant lymphadenopathy  
3. 
Completed at least 6 weeks of chemotherapy consisting of FOLFIRINOX, 
mFOLFIRINOX, and/or a gemcitabine-based doublet regimen prior to start of SBRT. 
Other variations such as FOLFOX or FOLFIRI are also acceptable; any other variations 
must be discussed with the Medical Monitor prior to randomization.  
4. 
Remain non-metastatic as confirmed by a CT scan at screening 
5. 
Female or male subjects ≥ 18 years of age 
6. 
ECOG performance status of 0-2 
7. 
Adequate end-organ function, based on routine clinical and laboratory workup: 
a. ANC > 1,000 cells/µl, platelets ≥ 75,000 cells/µl, hemoglobin ≥ 7.0 g/dl 
b. Calculated creatinine clearance ≥ 30 ml/min 
c. Total bilirubin ≤ 2.5 × ULN, AST and ALT ≤ 3 x ULN 
d. International normalized ratio (INR) or prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving 
anticoagulant therapy 
8. 
Males and females of childbearing potential must agree to use highly effective 
contraception starting prior to the first day of treatment and continuing for 30 days 
(females) and 90 days (males) after the last dose of GC4711 or placebo (Appendix 8))  
9. 
Ability to understand and the willingness to sign a written informed consent form (ICF) 
 
Exclusion Criteria 
1. 
Subjects with documented metastatic disease using standard work-up (per investigator) 
at diagnosis and/or at the screening response evaluation 
2. 
First-line chemotherapy other than FOLFIRINOX, mFOLFIRINOX, and/or a 
gemcitabine-based doublet regimen.  Subjects receiving either regimen after initial 
gemcitabine monotherapy are eligible.  
3. 
Prior abdominal RT with substantial overlap in radiation fields as determined by the 
treating radiation oncologist 
4. 
Subjects not recovered/controlled from treatment-related toxicities judged by the local 
investigator 
5. 
Uncontrolled malignancy other than PC that requires active treatment 
6. 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to GC4711 
7. 
Uncontrolled gastric or duodenal ulcer disease within 30 days of dosing 
8. 
Visible invasion of bulky tumor into the lumen of the bowel or stomach on endoscopy 
(Note: Radiological or superficial bowel infiltration is allowed, unless deemed clinically 
unsafe). 


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9. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection requiring an inpatient stay or delay of therapy, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that, in the opinion of the investigator, would limit compliance with study 
requirements 
10. 
Subjects Gilbert syndrome who are homozygous for the UGT1A polymorphism. 
11. 
Subjects with hypokalemia whose QT/QTc interval > 470 ms (for women) and > 450 ms 
(for men) on the screening ECG at visit 
12. 
Treatment with any investigational drug outside this protocol since diagnosis until 
disease progression given for the disease in study.  Prior to the randomization of subjects 
on other investigational agents, Sponsor’s written approval must be obtained. 
13. 
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 
14. 
Female subjects who are pregnant or breastfeeding 
15. 
Any other conditions that, in the investigator’s opinion, might indicate the subject to be 
unsuitable for the study 
16. 
Subjects who have already undergone resection of their pancreatic tumors. 
5.2  Screen Failures 
Initial eligibility determination will be at the discretion of the treating investigator and discussion in 
the site’s institutional multidisciplinary group, following NCCN v1.2020 guidelines (Appendix 5) 
for diagnostic criteria of unresectable or borderline resectable PC and standard work-up for 
documentation of distant disease. The Medical Monitor will be available for discussion regarding 
eligibility criteria.  
A subject is considered as a screen failure if the subject signs the ICF but withdraws consent or is 
deemed ineligible prior to randomization. The reason why the subject was precluded from the 
clinical study will be recorded in the eCRF. Individuals who do not meet the criteria for 
participation in this study (screen failure) may be rescreened at a later date. 
5.3  Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Subject Study Withdrawal: In accordance with the Declaration of Helsinki, a subject has the right 
to withdraw from the study at any time for any reason. Subjects who withdrawal consent early 
should be encouraged to continue with survival and late toxicity follow-up, if feasible. 
 
Subject Study Discontinuation: The Investigator or Sponsor may also, at his/her discretion, 
discontinue a subject from participating in this study at any time.  
 
Study Intervention Discontinuation: A subject may discontinue study intervention but remain in 
the study for follow-up for any of following reasons:  


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• 
A protocol violation (reason must be specified, for example: lack of compliance, use of 
a prohibited concomitant medication, failure to meet inclusion/exclusion criteria after 
study entry, etc.) 
• 
The subject was “lost to follow-up” 
• 
Unacceptable adverse event necessitating treatment cessation (Grade 4 or recurrent 
Grade 3 adverse event related to GC4711/placebo). 
• 
More than three infusion modifications of GC4711/placebo 
• 
Subject requests to withdrawal from the study treatment 
• 
Subject becomes pregnant  
• 
Other reasons (reason must be specified, for example: the subject moved, investigator 
decision, Sponsor decision to terminate trial, etc.) 
 
If a subject discontinues from the study treatment early (did not complete all 5 fractions of SBRT), 
they will continue to be followed for progression, toxicities and survival as outlined in the SOA.  
 
The primary reason and date for ceasing treatment, discontinuation and/or subject withdrawal will 
be clearly documented in the subject’s medical record and recorded on the appropriate CRF 
page.  
6 STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study protocol. 
Refer to the GC4711 IB for more detailed information regarding the storage, preparation, 
destruction, and administration of each treatment. 
6.1  Investigational Product: GC4711  
 Dosage Formulation and Preparation 
GC4711 IV drug product is formulated as a lyophilized solid in a vial and reconstituted shortly 
before administration with a provided 26 mM sodium bicarbonate aqueous buffer diluent. Sterile 
drug product and diluent will be provided by Galera Therapeutics Inc., and the drug product will be 
supplied as 120 mg in 3 mL clear glass vials and reconstituted by adding 1.10 mL of the provided 
diluent to yield 100 mg/mL reconstituted drug product. Note that this volume takes into 
consideration the expansion of the diluent on dissolution of the lyophilized GC4711, to give the 
indicated concentration. GC4711 (reconstituted solution) will be prepared by the unblinded 
pharmacist, diluted in normal saline (0.9% NaCl) to obtain a 100 mL dosing solution for IV 
infusion. 100 mL Normal saline (0.9% NaCl) for IV infusion, supplied by the site, will be used as 
placebo.  
 GC4711 Dosage, Administration, and Schedule 
Arm A: 100 mg/day of GC4711 will be given via IV infusion over 15 minutes (+5 minutes), prior 
to each SBRT dose, from the first to the last SBRT treatment (5 doses). On days of SBRT, 


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GC4711 will be administered with a maximum of 180 minutes between the end of infusion 
and the start of SBRT.  
Arm B:  Placebo (normal saline) will be administered via IV infusion over 15 minutes (+5 minutes) 
to be completed with a maximum of 180 minutes prior to SBRT as for Arm A. 
A total of 100 mL of GC4711 or Placebo (normal saline) will be infused IV over a 15-minute period 
using a programmable pump, when feasible. Each infusion should be given before each of the 5 
SBRT treatments, and all treatments should occur within a 10-day window. (See Table 1: Schedule 
of Assessments) 
 GC4711 Handling/Storage/Accountability  
Study drug will be administered under the supervision of study site personnel. The infusion volume 
and timing of each dose will be recorded. A separate study Pharmacy Manual will provide 
additional details for preparation/handling/storage and accountability.  
 GC4711 Drug Packaging and Labeling 
GC4711 with diluent will be provided by Galera as single-use vials for daily doses to be 
administered via IV infusion concurrent with SBRT. The drug product is supplied as 120 mg in 3 
mL clear glass vials along with 26 mM sodium bicarbonate buffer diluent which is packaged in a 3 
mL clear glass vial. Each vial will be labeled with the appropriate language, including the required 
regulatory text.  
Normal saline will be provided and prepared by the local site pharmacy for subjects assigned to 
placebo.   
 Maintenance of the Blind 
All staff at the site should be designated as either blinded or unblinded. 
Unblinded pharmacy staff will be responsible for management and accountability of investigational 
product and preparation of study drug in a blinded fashion.  The unblinded pharmacy staff will 
ensure the double-blind nature of this study and will not share the treatment assignment directly or 
indirectly (IP Accountability Logs, IV bag labels, etc.) with the blinded site staff.  Sites should be 
able to provide documentation regarding how the blind is maintained at their sites.  
The site pharmacists will obtain treatment assignments for subjects via the Randomization and Trial 
Supply Management System (RTSM) through their unique username and password, which should 
not be shared. Blinded staff will not have access to the treatment assignments via the RTSM. 
Preparation of the assigned treatment group (GC4711 or placebo) can also be found in the 
Pharmacy Manual.    


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 Investigational Product Storage 
GC4711 should be stored in the pharmacy at or below -15°C. The sodium bicarbonate aqueous 
buffer diluent will also be stored in the pharmacy. The diluent must be stored under refrigerated 
conditions (2 to 8ºC) and must not be frozen. The storage temperature should be monitored and 
recorded daily as per site SOPs to ensure temperatures are maintained as per above. Copies of 
temperature monitoring logs will be made available to the CRA upon request. The Sponsor must be 
notified of any deviation from the specified storage conditions.   
Study drug must always be kept in a secure place with access limited to the unblinded pharmacy 
staff under the appropriate storage conditions.  All personnel involved in the dispensing of study 
drug should be aware of its location.  Any deviations in accountability and/or storage should be 
reported to the site CRA immediately.  
 
 Study Intervention Compliance 
Study drug will be administered under the supervision of study site personnel. The infusion volume 
and timing of each dose will be recorded. Accidental overdoses should be reported to the 
Sponsor/designee promptly (see Section 8.4.7). 
 
6.2 Concomitant Medications  
Investigators may prescribe concomitant medication or supportive care as deemed necessary. All 
such current medications taken, including anti-emetics, steroids, and anti-tumor treatments, as well 
as any (surgical) interventions will be recorded from 30-days prior to dosing of GC4711/placebo 
through 3 months after completion of SBRT. After the 3 Month follow up visit, only medications 
used to treat late radiation toxicities should be recorded through 1 year (or distant disease 
progression, whichever comes first), including inhalers, steroids, oxygen supply, etc.  Additionally, 
any new anti-cancer therapy given at any point during follow-up (including survival follow-up) 
should be recorded in the CRF through 36 months post-SBRT.  
6.3 Drug Interactions 
 CYP2D6 Substrates 
The clinical potential of GC4711 to increase the concentration of drugs that are CYP2D6 substrates 
has not yet been studied. However, a GC4711 analogue also in clinical development, GC4419, has 
demonstrated preclinically and clinically to be a strong inhibitor of CYP2D6. It is   recommended to 
avoid concomitant use of GC4711 with CYP2D6 substrates where minimal increases in 
concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities (substrates 
with a narrow therapeutic range or are strong inhibitors of CYP2D6).  
 
The following medications are classified as strong inhibitors of CYP2D6 (drugs that cause a ≥ 5-
fold increase in the plasma AUC values or more than a 80% decrease in clearance): bupropion, 
fluoxetine, paroxetine, and quinidine.  (https://drug-interactions.medicine.iu.edu/MainTable.aspx) 


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The following medications are classified as CYP2D6 substrates with a narrow therapeutic index:  
dosulepin, flecainide, sotalol, pimozide, procainamide, theophylline, trabectedin, enasidenib, 
erlotinib, idarubicin, ixazomib, tamoxifen, rucaparib, dacomitinib, clonidine, desipramine, 
clomipramine, amitriptyline, imipramine, notriptyline, trimipramine, bortezomib, amoxapine, 
dronedarone, astemizole, ponatinib, phenytoin, doxorubicin.  
https://go.drugbank.com/categories/DBCAT004031.   
 
In addition, inducers or strong inhibitors of CYP2D6 should be avoided in conjunction with 
administration of GC4711.  A list of such inducers and inhibitors may be found at: https://drug-
interactions.medicine.iu.edu/MainTable.aspx 
 
 OCT2, MATE1 and MATE2-K Transporters 
GC4711 was tested in vitro for its potential as an inhibitor or substrate for the human transporters 
organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE) 1, and 
MATE2K.  GC4711 demonstrated inhibition against 3 of the transporters, OCT2, MATE1, and 
MATE2K, all involved in the transport of organic cations (e.g., creatinine, metformin, and 
cimetidine).  The Cmax of GC4711 demonstrated potential to inhibit renal OCT2, MATE1 and 
MATE2-K transporters which could affect the clearance of other organic cation drugs.   
Based on this information caution should be used when administering the following OCT2, MATE1 
and MATE2K subtrates with a narrow therapeutic index concomitantly with GC4711:  topotecan, 
procainamide, baricitinib, niraparib, abemaciclib, tipiracil, flecainide, niraparib, cisplatin, 
oxaliplatin, dalfampridine, dofetilide, clofarabine and gentamicin.  
(https://go.drugbank.com/categories/DBCAT004582, 
https://go.drugbank.com/categories/DBCAT004525, 
https://go.drugbank.com/categories/DBCAT004526) 
In addition, caution should be used when concomitantly administering the following MATE2K 
inhibitors with GC4711:  tazemetostat, avapritinib, trilaciclib, capmatinib, fexinidazole, and 
olaparib. (https://go.drugbank.com/categories/DBCAT005491) 
 
6.4 Prohibited Medications 
Investigators may prescribe any concomitant medication or supportive care. All medications and 
new treatments will be reported in the follow-up visits through 3 months following SBRT 
completion, and medications associated with late toxicities will be reported until documented 
progressive disease. Supportive care includes anti-emetic prophylaxis, hematopoietic growth factors 
used according to ASCO guidelines, systemic antibiotics, hydration to prevent renal damage, or 
other treatments, consistent with local standard of practice. GC4711 may cause mechanism-related, 
transient hypotension, or lightheadedness.  
Because of the potential for such mechanism-related toxicities, the following drugs that could 
precipitate drops in blood pressure, should not be taken by patients while receiving GC4711: 


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• Nitrates (sublingual, oral or transdermal nitroglycerin; oral isosorbide mono- or dintitrate)  
 
• Phosphodiesterase type 5 (PDE 5) inhibitors (sildenafil, tadalafil, vardenafil, avanafil). 
 
• Alpha adrenergic blocking agents prescribed for hypertension, benign prostatic hypertrophy, 
prostate cancer treatment effects, and peripheral artery disease (doxazosin, prazosin, terazosin, 
tamsulosin, alfuzosin, silodosin, phenoxybenzamine, phentolamine). 
 
• 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 GC4711 or 
placebo. 
 
• Treatment with any investigational drug outside this protocol since diagnosis until disease 
progression given for the disease in study (e.g., chemotherapy, immunotherapy, targeted 
therapy, hormone therapy, and biologic therapy).  Prior to the randomization of subjects on 
other investigational agents, Sponsor’s written approval must be obtained. 
 
If nitrate-based medication was replaced by alternative treatment or stopped by the local 
investigator before study entry, subjects can restart their regular medications 24 hours after 
completion of GC4711 or placebo treatment. 
Patients on antihypertensives should take their hypertensive medications separated by several hours 
from GC4711.  As an example, if GC4711 is to be administered early in the day, any 
antihypertensive medication should be administered later in the day.  Drugs that have the capacity 
to cause precipitous drops in blood pressure should be avoided. 
In addition to the above, a single patient with a history of myasthenia gravis and carotid sinus 
sensitivity developed severe symptomatic bradycardia associated with nausea and hypotension after 
receiving GC4419. Given that GC4711 is an analog of GC4419, GC4711 should be used with 
caution for patients with a clinical history or with medication requirements that may place them at 
risk for being unable to mount a physiologic tachycardia to decreases in blood pressure. 
6.5  Anticipated toxicities 
 Anticipated Toxicities of GC4711 
Per the IB, the following individual AEs observed in healthy volunteer studies are listed and 
considered “expected” after GC4711 infusions: 
• 
lightheadedness, dizziness, faintness, or mild decrease in blood pressure  
• 
mild facial tingling 
• 
nausea 
• 
headache 
• 
pain, bruising, or redness at the spot where GC4711 was being given by IV 
• 
pain or discomfort in the arm into which GC4711 was being given by IV 


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• 
fatigue  
 Toxicity Management/Infusion Modifications  
Any subject who receives treatment with GC4711/Placebo on this protocol will be evaluable for 
toxicity. Each subject will be assessed for the development of toxicity according to the SOA (Table 
1). Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0.  
Toxicities that will require infusion modification of the GC4711 or placebo administration include 
the following: 
• Grade 2 or greater hypotension occurring within 1 hour of the end of GC4711 or placebo 
infusion 
• Other Grade 3 or greater AEs judged by the investigator to be possibly attributable to the 
study infusion. 
Patients who experience a toxicity noted above during or shortly after the infusion of 
GC4711/placebo should have their infusion times increased to 30 minutes (+5 minutes).  
If the toxicity recurs, the infusion time should be increased to 45 minutes (+5 minutes), and may be 
increased to 60 minutes (+5 minutes) if hypotension occurs with a 45-minute infusion.  
If toxicity occurs with a 60-minute infusion, the patient should be discontinued from further 
treatment with GC4711/placebo but should remain on study for all other protocol interventions 
(SBRT) and assessments.     
 Anticipated Toxicities of SBRT 
PC by itself can also induce many symptoms (e.g., abdominal pain, bleeding, and obstruction), 
stressing the fact that disease progression needs to be excluded before relating these symptoms to 
treatment. All subjects are exposed to multi-modality treatment and therefore are at risk to 
accumulate different toxicities from chemotherapy, SBRT, and surgery as well (Jaoude 2020, 
Reyngold 2019). Explaining the risk of local high dose RT delivery is important for each individual 
subject. The following adverse events are used in the protocol and informed consent form based on 
Common Toxicity Criteria (CTCAE) version 5 (Table 3). 
Very likely (80-90%): 
• Fatigue (which generally goes away after the radiation therapy is completed)  
• Abdominal pain, discomfort 
• Nausea, loss of appetite 
Less likely (30%): 
• Temporary changes in blood work (decrease in blood counts, increase in liver enzymes), 
without symptoms  


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• Vomiting (during therapy)   
• Diarrhea 
• Ulcers 
• Skin irritation, redness, itchiness, discomfort  
• Pain 
• Breathing discomfort, hick-ups 
Nausea and vomiting may be managed with standard anti-emetic regimens (5-HT3-receptor 
antagonists, NK1 receptor antagonists); diarrhea may be managed with standard anti-diarrheal 
agents (loperamide); pain/abdominal pain may be managed with routine analgesics.  Changes in 
blood counts should be carefully followed and patients transfused with blood products as 
clinically indicated or treated with prophylactic antibiotics in the event of neutropenia.  Skin 
irritation may be managed with dermatologic lubricants (e.g., aloe).   
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 subjects with large tumors and/ 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. 
• Spinal cord injury 
Risk of rare but serious events is more prominent in subjects who did experience toxicities 
during chemotherapy or using co-medications for co-morbidity. Early signs of pain, obstruction 
and anemia need to be closely monitored and ulcers/bleeding treated with proton inhibitors or 
surgically if needed 
 
Table 3: Expected acute and late SBRT toxicities summarized 
Acute: 
• Abdominal pain 
• Nausea, vomiting 
Late: 
• Liver failure 
• Kidney failure 


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• Diarrhea 
• Gastric/duodenal ulcers 
• Loss of appetite 
• Fatigue  
• Skin changes  
• Pain  
• Recurrent hick-ups 
• Renal/Liver dysfunction 
• Anemia, thrombopenia, neutropenia 
• Abdominal bleeding 
• Bowel stenosis, obstruction, or 
perforation 
• Persisting thrombopenia, anemia 
• Spinal cord injury 
 
 
 Anticipated Complications of Surgery 
Overall, 50% of the borderline resectable and 30% of the unresectable subjects are expected to be 
surgically explored. Surgery can be performed within 8 weeks after SBRT or in a later stage if 
awaiting greater mass reduction or need for a palliative intent (e.g., bypass for obstruction).  
Pancreatic surgery is known for 30-day mortality rates of 5%, which are lower in high-volume 
medical centers (Bradley 2002). The most common causes of mortality are gastric ischemia, post-
pancreatectomy hemorrhage, pneumonia, liver ischemia, abdominal infection, and sepsis with 
multi-organ failure. The additional 90-day major morbidity rate is around 25%, most often featuring 
delayed gastric emptying, post-pancreatectomy hemorrhage, and pancreatic fistulas or postoperative 
organ space infections (Klompmaker 2019). 
 Anticipated Complications of Chemotherapy 
Most common Grade 3-4 AEs following FOLFIRINOX are (febrile) neutropenia, 
thrombocytopenia, anemia, fatigue, nausea, diarrhea, vomiting, neuropathy, and increased ALT 
(Suker 2016). In this protocol, modified FOLFIRINOX is proposed because it offers comparable 
survival benefits with fewer AEs compared to the conventional dosage (Tong 2018).  
In subjects treated with gemcitabine-doublets (e.g., combinations with cisplatin or 5FU- or targeted 
therapies) Grade 3–4 toxicities, neutropenia, febrile neutropenia, and nausea were reported lower, 
while neurotoxicity and anemia were lower with FOLFIRINOX (Pusceddu 2019, Chiorean 2019). 
 Chemotherapy dosing adjustments 
Subjects will receive at least 6 weeks of chemotherapy prior to evaluation for SBRT consisting of 
FOLFIRINOX, mFOLFIRINOX, or a gemcitabine-based doublet regimen (e.g., gemcitabine 
combined with nab-paclitaxel, cisplatin, capecitabine). Many subjects will need dose reduction 
and/or simplification of their chemotherapy regimen throughout the period of chemotherapy 
administration; all such changes will be made at the discretion of the investigator and based on the 
full-prescribing information for each individual agent and accepted standards of medical 
practice/NCCN guidelines for the administration of FOLFIRINOX/mFOLFIRINOX or 
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7 STEREOTACTIC BODY RADIATION THERAPY (SBRT) 
7.1  SBRT Principles 
All subjects will be evaluated by the treating radiation oncologist at the local site. Based on location 
and size of the tumor, dose planning will be determined by clinical appropriateness that balances 
ablation of the lesion(s) and corresponding macroscopic tumor areas (GTV), while respecting 
normal tissue constraints.  Details of the radiotherapy treatment can be found in the RTQA manual.  
7.2  Treatment schedule 
The start of SBRT must be at least 7 days but maximum 42 days after last chemotherapy cycle is 
given (the 7 – 42 day window will begin at the end of the treatment cycle, not on the last day of 
actual treatment). Treatments may start on any day, given sequentially within a 10-day window. 
Fractions should be given sequentially daily within 180 minutes of the end of the infusion of 
GC4711 or placebo. Between fractions, a minimum of 18 hours and a maximum of 72 hours is 
permitted. Additionally, an occasional 96-hour window is acceptable (i.e. in case of a holiday or 
machine breakdown). All 5 fractions should be given within a maximum of 10 calendar days. If a 
subject is unable to receive their treatment within 10 days, the Medical Monitor and Galera study 
team should be notified.  
If SBRT administration is interrupted on any given day due to a machine breakdown or other 
unforeseen circumstances, the rest of the treatment or a new SBRT session must be given as soon as 
possible. Rescheduling and SBRT dosing in case of machine problems will be determined by the 
patient’s treating physician in accordance with standard of care and covered with extra GC4711 
dosing. In case of machine breakdown during scheduled dosing, a 6th fraction and dose of GC4711 
or placebo may be given.  
Prescription of proton inhibitors for each subject is strongly recommended. Anti-emetic and anti-
diarrheal prophylaxis and hematopoietic growth factor use should be administered per ASCO 
guidelines. 
7.3  Quality Review 
Each participating center will provide SBRT certification, and all radiation treatment plans will be 
centrally reviewed.  
 
Radiation plans for all subjects will be reviewed per site by the local investigator prior to treatment 
start. Signing off can be done by another radiation oncologist in the same institution but is preferred 
to be done by both the treating physician and the local investigator.  
 
All treatment plans will be reviewed for quality assurance according to the standard review process 
at each participating institution, including quality assurance of the plan.  
 


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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.  
 
After internal validation, the RTQA group will perform a quality check on the first 2 subjects’ 
treatment plans before start of treatment and all other plans in a retrospective manner per the RTQA 
Manual. 
 
The RTQA group will work with all sites at site initiation to ensure consistency in RT among 
participating centers, including discussion of standard cases, SBRT experience, motion management 
approach and planning rules.  
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SOA (Table 1).  
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SOA, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as applicable. 
A previously performed CT scan, MRI scan, safety blood work (serum chemistry and complete 
blood work) or other study assessments done per standard of care may be utilized for screening if 
done within 28 days prior to randomization. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes, provided that 
the procedures met the protocol-specified criteria and were performed within the time frame defined 
in the SOA.  
8.1 Imaging protocols 
 CT imaging 
Staging and disease response evaluation will be performed by CT scan according to the SOA. Both 
local and central review reading will be based on RECIST 1:1 (Eisenhauer 2009), see Appendix 2). 
CT scans are reported following the outline of the Imaging Manual and will drive trial inclusion and 
treatment decisions. Images should be performed with IV contrast, if possible (i.e., no allergies and 
appropriate kidney function), and with a slice thickness of 5 mm or less. All CT-imaging will be 
interpreted locally by the investigational site radiologist and retrospectively centrally reviewed. In 
case of allergies to IV contrast, MRI or PET/CT are allowed for response evaluation measurements. 
The same method of imaging used at baseline should be used at each follow-up evaluation for 
evaluation of treatment response, if possible (see Imaging Manual). 


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In case the CT-scan at 4 weeks after SBRT shows local progression, confirmation will be needed at 
the next scheduled imaging timepoint at Month 4 to exclude the risk of pseudo-progression after 
SBRT (Ma 2019), based on post-RT inflammatory reactions. 
 MRI imaging 
MRI imaging (at 1.5 or 3.0 Tesla) is used in the protocol for the local judgement in the 
multidisciplinary group upon: 
1) definition of unresectable versus borderline resectable disease (see Imaging Manual),  
2) SBRT feasibility and planning, and  
3) evaluation of technical resectability 4 weeks after completion of SBRT (confirming a 
tissue plane between the tumor and normal structures excluded from Whipple resection (e.g., 
large vessels). 
The MRI images will be collected and centrally reviewed retrospectively.  
For RT planning, the T1 sequences are important for the GTV delineation, while the T2 can show 
tumor invasion in vascular and bowel structures to be included in the CTV. Aside of the target 
volumes, the OARs are contoured on CT images (4D acquired), see RTQA Manual for more 
information. 
When MRI is contraindicated, a CT scan is acceptable if fiducials have been placed. 
8.2 Efficacy Assessments   
 Definitions for Response Evaluation 
8.2.1.1 
Overall Survival 
The OS is defined as the time from randomization to death due to any cause. Survival status will be 
collected as defined by the SOA. Subjects will be followed for survival status every 3 months until 
2 years then every 6 months through 3 years post-SBRT completion. All subjects who are in the 
Survival Follow-up and not known to have died prior to Sponsor requests for additional survival 
status timepoints may be contacted at that time to confirm survival status. 
8.2.1.2 
Progression-Free Survival 
The PFS is defined as the time from the date of randomization to first occurrence of local and/or 
regional progression, distant metastases (=PD), or death due to any cause, whichever occurs first. 
8.2.1.3 
Local and Regional Control 
Local and regional control is defined as the time from randomization to any local and regional 
recurrence or progression (in RECIST 1.1 reported as target lesions). Local enlargement, marginal 


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failures, involved nodal failure, or local failure (see below) will be considered failure events for 
local and regional control. Regional failure (see below) will be a failure event for local and regional 
control. Distant metastases are not considered local progression. Patients who die without 
progression of PC will be considered non-failures for local and distant progression and will be 
censored as of the data of their last imaging assessment which demonstrated progression free.  
8.2.1.4 
Time to Distant Metastatic Disease 
TDM rate refers to the time from randomization to cancer that has spread from the original 
(primary) tumor to distant organs (in RECIST 1.1 addressed as any new lesion).  
8.2.1.5 
Best Overall and In-Field Response 
The best overall response is determined once all the data for each subject is known. The best overall 
response is the best response recorded from randomization until disease progression/recurrence 
across all time points (for example, a patient who has SD at first assessment, PR at second 
assessment, and PD on last assessment has a best overall response of PR). Best overall response 
rates will take both target (pancreas lesion and up till 5 nodal lesions taken together) and 
development of new non-target lesions (distant lesions) into account, taking as reference for 
progressive disease the smallest measurements recorded since the treatment started. Best in-field 
response is defined as the best response from randomization across all time points and considers the 
defined target lesions only.  
 
8.2.1.6 
Resection rates 
Surgical resection is known as the main prognostic driver for survival (Mellon 2015, Jaoude 2020). 
In both arms, the number of subjects judged by each institution’s multidisciplinary group after 
SBRT as “technically resectable” will be counted. Margin status will be documented as R0 
(negative) or R1 (positive). Not all subjects, who are surgically explored, will be resected, and the 
reasons for this will be documented. 
 
The proportion of all randomized subjects in whom R0 or R1 resection is achieved will be 
compared among arms. Response is classified as unresectable (no resection performed), pNC (no 
response as observing more than 30%  residual tumor cells in the specimen), pPR (partial response 
as ≥ 5% to 30% residual tumor cells) pNR (near complete response as 1 to < 5% residual tumor 
cells) and pCR (complete response as 0% residual tumor cells).  
 
8.2.1.7 
CA19.9 normalization 
Normalization is defined as reaching the value of <37 U/ml from screening across all follow-up 
time points. Three categories are defined: normalization throughout 6 months, decrease of >30% but 
no normalization and increase over 90 U/ml before 6 months or no significant decrease (<30%). 
Distribution into these categories will be compared across the two arms and related to resection 
rates and survival. 
 


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8.3 Safety Assessments 
Planned time points for all safety assessments are provided in the SOA (See Appendix 4 for 
definitions and Table 1 for timing). 
 Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, GI, and neurological systems. Weight will also be measured and recorded. Height 
should only be recorded at screening. The physical examination should be performed by a physician 
or health professional and licensed to perform physical examinations. 
 Vital Signs 
Vital sign measurements prior to each infusion will include pulse rate, respiratory rate, systolic and 
diastolic blood pressure, and temperature. Pulse and blood pressure readings will be taken within 
15-minutes prior to and after each infusion. The subject should be at rest (seated or supine) for 2-5 
minutes prior to taking the vital signs.  
 Electrocardiograms 
A 12-lead ECG recording will be conducted using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. The recordings should be as close as 
possible to corresponding PK sampling (see the SOA, Table 1) ± 10 minutes from the PK blood 
draw. The pre-dose and post-dose ECG should be done in triplicate with a single ECG at the 24-
hour timepoint prior to the next dosing. 
8.4 Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
All AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following up 
AEs that are serious, that are considered related to the study intervention or study procedures, or 
that caused the participant to discontinue the study intervention/study. 
 Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information 
All AEs/SAEs will be collected for all subjects from the Day 1 dosing through 90 days post-SBRT. 
Ongoing SAEs at 90 Days post-SBRT will be followed through resolution. After 90 days post-
SBRT, AEs/SAEs associated with late toxicities will be followed through 1 year post-SBRT or until 
distant disease progression (see Table 3, Section 8.4.6). 


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All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 4. The investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available. Specific SAE reporting 
instructions are provided in a separate manual.  
 Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 4. 
 Regulatory Reporting Requirements for Serious Adverse Events 
1. Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
2. The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and investigators. 
3. Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
investigators, as necessary. 
4. An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
 Pregnancy 
The risks of treatment with GC4711 during pregnancy have not been evaluated. Male subjects and 
female subjects of childbearing potential who engage in sexual intercourse should use a highly 
effective method of contraception throughout the study and for 30 days (females) or 90 days (males) 
following the last dose of GC4711 or placebo. If a pregnancy is reported, the investigator should 
inform the Sponsor within 24 hours of learning of the pregnancy and should follow the procedures 
outlined in Appendix 8. 
 


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 Late Toxicities 
Late toxicities will be collected as per the SOA. Late toxicities (See Section 6.4) are collected from 
90 days through 1 year after SBRT completion (see Table 3 for distinction acute versus late and 
most common AEs). Collection will be stopped after documented distant disease progression, 
because of accumulation of symptoms generated by disease and/or sequential treatments. Late 
toxicities scored are restricted after 90 days of follow-up to and defined as below using CTCAE 
(version 5.0): 
1. Grade 2-5 GI events, including bowel stenosis, obstruction, or perforation 
2. Grade 3-5 spinal cord/brachial plexopathy and vascular events 
3. Grade 3-5 persisting hematological disorders 
4. Grade 3-5 general disorders as fatigue, anorexia 
5. Grade 3-5 liver or kidney injury or failure 
 Treatment of Overdose 
Study drug overdose is any accidental or intentional use of study drug in an amount higher than the 
dose indicated per protocol for a given subject. Any study drug overdose during the study should be 
noted on the study medication eCRF.  
All AEs associated with an overdose should both be entered on the Adverse Event eCRF and 
reported using the procedures detailed in 4. If the AE associated with an overdose does not meet 
seriousness criteria, it must still be reported using the Galera Therapeutics Clinical Trial Report 
Form for SAEs and in an expedited manner but should be noted as non-serious on the form and the 
Adverse Event eCRF.  
There is currently no specific treatment in the event of an overdose of GC4711. The investigator 
will use clinical judgment and standard supportive care to treat any overdose. 
 Misuse/Abuse 
Any AEs associated with misuse or abuse will be appropriately reported as AEs or SAEs and 
monitored per Section 8.4.3 and 4. 
8.5  Pharmacokinetics 
PK sampling for GC4711 and its two metabolites GC4752 and GC4757 will be performed on all 
subjects. Blood sampling will be performed along with the ECGs on the days and times indicated in 
the SOA (Table 1) and outlined Table 4 below. 
Table 4: PK Draw and ECG Windows 
PK blood draw 
PK draw window 
ECG  
Pre-dose 
- 1 hour from start of 
infusion 
±10 minutes of PK draw 
(triplicate) 
EOI 
+ 10 minutes from EOI 
±10 minutes of PK draw (triplicate) 


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24-hours After Dose 
± 1 hour from EOI or prior 
to dosing if delivered on 
next sequential day 
±10 minutes of PK draw 
(single) 
Abbreviations: EOI=end of infusion; PK=pharmacokinetics. 
Refer to PK Manual for additional details on PK sample collection.  
9 STATISTICAL CONSIDERATIONS 
This section provides a high-level overview of the planned statistical analyses of the trial. A 
separate statistical analysis plan finalized before the database lock will include the full analytic 
details. In cases where the statistical analysis plan and this statistical section of the protocol differ, 
the details in the statistical analysis plan will guide the final analysis of the data. 
9.1  Sample Size Calculation 
The intended enrollment for the study is 220 patients. The sample size calculation is based on the 
primary endpoint of OS. Median OS in the control arm (placebo + SBRT) is estimated to be 
approximately 11 months from randomization (Mellon 2015, Krishnan 2016, Hammel 2013). 
Treatment with GC4711 + SBRT is expected to result in a 45% reduction in the OS hazard rate, 
which corresponds to an increase in median OS to 20 months assuming exponential survival. 
To ensure 90% power to test the null hypothesis: OS hazard ratio = 1, versus the specific alternative 
hypothesis: OS hazard ratio = 0.55, 120 deaths need to be observed, assuming a two-sided Type I 
error rate of 5% and randomization at a 1:1 allocation ratio. To allow an interim analysis for benefit 
after 84 deaths (i.e., at roughly 70% information time) 120 deaths must be observed to maintain 
90% power.  
9.2  Randomization/Blinding 
All subjects, investigators, and study personnel involved in the conduct of the study, including data 
management, Sponsor, medical monitoring, the study monitor, contract research organization 
(CRO) personnel, and blinded statisticians, will be blinded to treatment assignment. The dispensing 
site study personnel will be unblinded. An unblinded Study Monitor will be assigned to the study 
for confirming drug accountability and monitoring at the site’s pharmacy. The statistician who 
prepares the master randomization schedule will be unblinded as will the statistical reporting group 
that prepares safety and efficacy reports for the Data Monitoring Committee. Additional unblinding 
may include drug supply/RTSM staff, pharmacovigilance, and regulatory affairs as needed to 
comply with reporting requirements. The master randomization schedule will be saved in an access-
controlled location to maintain the study blind.  
Section Treatment assignment should remain blinded until analyses of the primary efficacy results 
of the study have been performed on the final, locked data through the end of post-SBRT follow-up 
for all subjects. Only in the case of an emergency, when knowledge of the investigational product is 
essential for the clinical management or welfare of the subject, may the investigator unblind an 
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safety and efficacy analyses. The investigator will, whenever possible, discuss options with the 
Medical Monitor or appropriate Sponsor/CRO study personnel before unblinding. If the blind is 
broken for any reason and the investigator is unable to contact the Sponsor prior to unblinding, the 
investigator must notify the Sponsor/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 subjects remaining in the study.  
If an SAE is reported to the Sponsor/CRO, the Sponsor/CRO staff may unblind the treatment 
assignment for the individual subject. If an expedited regulatory report to one or more regulatory 
agencies is required, the report will identify the subject’s treatment assignment, consistent with 
applicable regulations for the territory in which the report is made. When applicable, a copy of the 
regulatory report may be sent to investigators in accordance with relevant regulations, the Sponsor 
policy, or both. 
Randomization codes are generated and assigned using a Randomization and Trial Supply 
Management System, and electronic access to the randomization codes will be granted for 
unblinded team members or in cases where the treatment assignment is needed by the 
Pharmacovigilance/Safety team, risk management, or drug supply oversight by unblinded team 
members. 
9.3  Analysis Populations 
The primary efficacy population will include the intent to treat (ITT) population of all randomized 
subjects; the primary efficacy analysis will be performed on the primary efficacy population. The 
safety population will include all randomized subjects who receive any study drug (i.e., GC4711 or 
placebo). A "per protocol" efficacy analysis, limited to the safety population, may also be 
performed. Subjects will be analyzed according to the treatment (GC4711/placebo) and strata used 
at randomization. Stratification for borderline resectable versus unresectable will be based on the 
primary diagnosis as judged by the multidisciplinary group using NCCN v1.2020 guidelines 
(Appendix 5) before start of chemotherapy. Medically inoperable subjects and subjects refusing 
surgery will be included in the unresectable stratum. Survival is reported to be similar for 
(m)FOLFIRINOX or gemcitabine-doublet used in first line, therefore no stratification will be used 
for choice of first-line chemotherapy regimen (Chiorean 2019, Pusceddu 2019).  
9.4 Analysis of the Primary Endpoint 
The primary objective is to determine whether treatment with GC4711 combined with SBRT 
prolongs OS compared to placebo combined with SBRT. 
 Definition of Primary Endpoint  
OS is defined as the time from randomization to the date of death due to any cause without 
consideration for whether subjects undergo resection following randomization. Subjects will be 
analyzed according to the treatment (GC4711/placebo) and strata used at randomization. 
Stratification for borderline resectable versus unresectable will be based on the primary diagnosis as 
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chemotherapy. Medically inoperable subjects and subjects refusing surgery will be included in the 
unresectable stratum. 
 
 Method of Analysis 
The primary efficacy analysis will be the comparison of OS between the two treatment groups using 
a stratified log-rank test at an overall two-sided 5% level of significance. The stratification will be 
based on the stratification factors as entered at randomization. The OS distribution will be estimated 
using the Kaplan-Meier method, and Kaplan-Meier curves, medians, and 95% confidence intervals 
of the medians will be presented for each treatment group. The hazard ratio for OS will be estimated 
along with its 95% confidence interval using a stratified Cox model using the same stratification 
values as for the log-rank test (Cox 1972).  
 
 Handling of Intercurrent Events 
The primary analysis will account for different intercurrent events as follows: 
1. Discontinuation of study treatment: survival data collected after treatment discontinuation 
will be used for the primary analysis regardless of the study treatment discontinuation 
reason. 
2. Surgical resection: because study treatment could affect the probability of undergoing 
surgical resection, data on vital status after surgical resection of the primary tumor will be 
collected and included in the primary analysis. 
3. Other anti-cancer therapy: survival data collected after initiation of other anti-cancer 
therapy will be included in the primary analysis. 
 Handling of Missing Values/Censoring/Discontinuations 
In the primary analysis, subjects who do not die will be censored at the date last known to be alive 
before withdrawal of consent, loss to follow-up, or study closure.  
 
 Sensitivity and Supportive Analyses 
In addition to the primary analysis, the OS hazard ratio and 95% confidence interval will also be 
assessed from analyses: 
1. that censor subjects following resection of their primary tumor 
2. that censor subjects after initiation of any other anti-neoplastic therapy 
3. of each level of randomization stratification factor. If the primary analysis is statistically 
significant, subgroup analyses to assess the homogeneity of the treatment effect across 
demographic and baseline disease characteristics may also be performed. Important 
subgroups will be specified in the statistical analysis plan. 


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9.5  Analysis of Key Secondary Endpoint 
PFS, the key secondary endpoint, is defined as the time from randomization to the date of first 
documented progression or death due to any cause. Progression will be measured by local and/or 
distant progression confirmed by centrally reviewed CT based RECIST 1.1.  
Assuming that the OS is significant, PFS may be formally tested at a two-sided 5% significance 
level. Other secondary endpoints will be analyzed descriptively.  
 Method of analysis of PFS 
PFS will be analyzed in a similar manner as the primary OS endpoint. 
 Handling of intercurrent events for PFS 
The analysis of PFS will account for different intercurrent events as follows: 
1. Discontinuation of study treatment: tumor assessment data collected after treatment 
discontinuation will be used for the primary analysis regardless of the study treatment 
discontinuation reason. 
2. Surgical resection: tumor assessment data and vital status after surgical resection of the 
primary tumor will be considered in the analysis of PFS. A sensitivity analysis may also be 
performed censoring subjects at last adequate tumor response assessment prior to resection. 
3. Start of other new anti-neoplastic therapies prior to disease progression: PFS events 
documented after the initiation of new anti-neoplastic therapy (aside from resection) will not 
be used for the primary analysis. A sensitivity analysis may be performed that considers 
such assessments after initiation of new therapy. 
 Handling of Missing Values/Censoring/Discontinuations for PFS 
In the main analysis of the endpoint, PFS will be censored on the date of the last adequate tumor 
assessment if no PFS event is observed. Because study treatment could affect the probability of 
undergoing surgical resection, PFS events documented after surgical resection of the primary tumor 
will be considered for the primary analysis provided tumor assessments continue. For subjects 
receiving a new anti-neoplastic therapy without prior progression, PFS will be censored on the date 
of the last adequate tumor assessment before the therapy. For subjects with PFS events observed 
after one or more missing or inadequate tumor assessments, PFS will be censored on the date of the 
last adequate assessment before the missing assessment(s). 
The statistical analysis plan will include a complete set of censoring rules. 
 Sensitivity and Supportive Analyses 
In addition to the main analysis of the endpoint, the PFS hazard ratio and 95% confidence interval 
will also be assessed from an analysis: 


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1. using the local investigators’ determination of progression 
2. censoring subjects after surgical resection 
3. that considers tumor assessment and vital status information collected after initiation of anti-
neoplastic therapies 
4. of each level of randomization stratification factor. If the overall analysis is statistically 
significant, subgroup analyses to assess the homogeneity of the treatment effect across 
demographic and baseline disease characteristics may also be performed. Important 
subgroups will be specified in the statistical analysis plan. 
9.6  Other endpoints 
Other secondary efficacy endpoints are local tumor control and distant metastasis-free survival, 
which will be summarized descriptively using time-to-event methods; overall and in-field tumor 
response over time, will be descriptively compared using a Cochran-Mantel-Haenszel test stratified 
by the strata used at randomization.  
 
Because surgical resection has been reported as associated with improved OS and PFS for this 
patient population (Mellon 2015, Jaoude 2020), the proportion of subjects with surgical resection 
will be documented and descriptively compared using a Cochran-Mantel-Haenszel test stratified by 
the strata used at randomization.  Surgical exploration rates, margin status (R0, R1) and pathologic 
response will be summarized and compared descriptively.   
 
Safety including both acute (for 90 days) and late (until distant progression or 1 year) toxicities, 
which will be summarized descriptively.   
 
Exploratory endpoints consist of changes in patient-reported symptoms (PRO-CTCAE; Basch 2014, 
Kluetz 2016, Appendix 6) as well as collection of CA19.9 values and normalization patterns, BRCA 
mutations, and pharmacokinetics will be summarized descriptively. 
 
9.7 Data Monitoring Committee (DMC)  
This trial will be monitored for safety and efficacy by an independent Data Monitoring Committee 
(DMC).  Based on its review, the DMC will make recommendations regarding the conduct of the 
study, i.e., to continue enrollment, to hold enrollment until further review, to amend the protocol, or 
to stop the study early. Details will be included in a separate DMC Charter.   
 DMC Interim Safety Analysis 
After 20 subjects have been randomized, the DMC will be convened to review safety data through 
the 4 week visit after SBRT. At this analysis, the DMC will review all unblinded safety data 
available and will consider a recommendation to continue the trial, to make modifications or to 
temporarily suspend enrollment and treatment, and consider study revisions for safety if more than 
4 subjects encounter a significant toxicity (section 10.8) in the experimental arm than in the control 
per arm.  The DMC will review as part of its safety review the frequency of unacceptable delays in 
SBRT administration in the two study arms.  For the purposes of this review, unacceptable delay 


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will be defined as EITHER a gap of 5 or more days between SBRT fractions OR a total SBRT 
delivery time (first to fifth fraction, inclusive) of more than 15 days.  The expected frequency of 
such delays in the control arm is 10%. If the DMC judges the frequency of such delays due to 
potential toxicity and not to other factors (e.g., disease progression, missed visits due to COVID-19) 
in the GC4711 arm to exceed twice that of the control arm, it will consider recommending 
modification of the trial. The DMC Charter will include details of the safety analysis. 
 DMC Interim Efficacy Analysis 
In addition to an interim test of superiority planned at N=84 deaths (70% information) as detailed 
below, a preliminary assessment will be performed at approximately N=36 events (30% 
information) to assess treatment effect and potentially result in decision to stop the trial early. 
Specifically, an observed hazard ratio exceeding 0.65 will support a decision to stop. Under 
exponential survival, an HR of 0.65 corresponds to a conditional power of 67% when the observed 
effect is assumed for the remainder of the trial.   No alpha adjustment to the 2 look O’Brien-
Fleming boundaries to assess superiority will be made.    
 
After approximately 84 deaths have occurred, the DMC will be convened to review efficacy data.  
The goal of the interim efficacy analysis is to allow early stopping of the trial for overwhelming 
superiority. Unblinded results from the interim analysis will not be communicated to the Sponsor 
unless the DMC recommends that 1) OS has crossed the pre-specified boundary of efficacy and the 
trial should be stopped for benefit. or 2) the study needs to be terminated for safety or risk-benefit 
ratio considerations.  
 
The pre-specified boundary will be calculated using a 2-look O’Brien-Fleming boundary as 
implemented using a Lan-DeMets alpha-spending function.  
 
9.8 Significant Toxicities 
Significant toxicities are defined (using the NCI-CTCAE grading scale) as Grade 3-5 AEs occurring 
from Day 1 through the 4 weeks’ visit post SBRT, and excluding the following: 
• AEs clearly related to disease progression or intercurrent illness   
• Grade 3 fatigue for 7 days or less,  
• Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and other 
supportive care 
• 
Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical interventions 
• Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis 
• Hematological grade 3-4 toxicities except for the following: 


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o Grade 4 neutropenia lasting >7 days.  
o Grade 3 thrombocytopenia with clinically significant bleeding. 
o Grade 4 anemia and grade 4 thrombocytopenia 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable International Council for/Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., participant 
recruitment advertisements) will be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, and all other applicable local regulations 
 Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with enough, accurate financial 
information, as requested, to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 


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responsible for providing information on financial interests during the study and for one year after 
completion of the study. 
 Informed Consent Process 
An initial Master-ICF-template sample ICF will be provided for the investigator to prepare the ICF 
to be used at his or her site. Updates to the sample ICF are to be communicated formally in writing 
from the Galera Trial Manager to the investigator. The written ICF is to be prepared in the 
language(s) of the potential subject population. 
The investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. Participants 
must be informed that their participation is voluntary. Participants or their legally authorized 
representative (defined as an individual or other body authorized under applicable law to consent, 
on behalf of a prospective participant, to the participant’s participation in the clinical study) will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before the 
participant was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
If the ICF is amended, participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 
The original signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
 Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or datasets 
that are transferred to the Sponsor will contain the identifier only; participant names or any 
information that would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 


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 Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRFs unless transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. The Sponsor or designee is 
responsible for the data management of this study including quality checking of the data. The 
Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract Research 
Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
 Source Documents 
Source documents include but are not limited to original documents, data, and records, such as 
hospital/ medical records (including electronic health records), clinic charts, lab results, subject 
diaries, data recorded in automated instruments, microfilm or magnetic media, and pharmacy 
records. At a minimum, all data required to be collected by the protocol should have supporting 
source documentation for entries in the eCRF, unless the protocol specifies that data can be 
recorded directly on/in the eCRF or other device.  
 Start and Closure of Study and/or Sites 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended termination. Reasons for the early closure of a 
study site by the Sponsor or investigator may include, but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 


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• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator will promptly inform the subject and must ensure appropriate subject therapy and/or 
follow-up. 
 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement. Authorship will be determined by mutual agreement and in 
line with International Committee of Medical Journal Editors authorship requirements. 
 
 


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APPENDIX 1: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the local laboratory at Baseline. Abnormal 
clinically significant local laboratory results including any collected outside of the protocol should 
be captured as Adverse Events.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5.1. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 5: Protocol-Required Safety Laboratory Assessments  
Hematology 
Biochemistry 
Other 
ANC 
Hemoglobin 
Hematocrit 
Red blood cell (RBC) Count 
White blood cell (WBC+diff) count  
Platelet count 
 
Blood urea nitrogen (BUN) 
Creatinine 
Creatinine clearance 
Glucose 
Potassium 
Sodium 
Calcium 
Chloride 
CO2 
Inorganic phosphate 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase 
(GGT) 
Total bilirubin (direct bilirubin 
reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
 
INR/PTT* 
CA19.9** 
Blood counts and chemistry labs collected at screening and the 4 week post-SBRT visit 
*INR/PTT only at screening 
**CA19.9 collected at follow-up visits through 1 year post-SBRT or until local or distant disease 
progression 
 
 
 
 
 
 


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APPENDIX 2: RECIST 1.1 Tumor Response Evaluation 
RECIST 1.1 Tumor Response Evaluation 
Definitions of the criteria used to determine objective tumor response for target lesions 
(Eisenhauer, 2009) 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression) 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
 


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APPENDIX 3: Reporting Guideline for Pancreas Imaging by CT and MRI 
The below information should be included in each CT and MRI report  
 
Morphologic Evaluation  
Appearance (in the pancreatic parenchymal phase): hypo-, iso-, or hyperattenuating  
Size (maximal axial dimension in centimeters): measurable or non-measurable (iso-attenuating 
tumors)  
Location (head right of SMV, body left of SMV): head/uncinate or body/tail  
Pancreatic duct narrowing/abrupt cutoff with or without upstream dilatation: present or absent  
Biliary tree abrupt cutoff with or without upstream dilatation: present or absent  
 
Arterial evaluation  
SMA: Present or absent  
Degree of solid soft tissue contact: ≤180° or >180°  
Degree of increased hazy attenuation/stranding contact: ≤180° or >180°  
Focal vessel narrowing or contour irregularity: present or absent  
Extension to first SMA branch: present or absent  
Celiac Axis: Present or absent  
Degree of solid soft tissue contact: ≤180° or >180°  
Degree of increased hazy attenuation/stranding contact: ≤180° or >180°  
Focal vessel narrowing or contour irregularity: present or absent  
CHA: Present or absent  
Degree of solid soft tissue contact: ≤180° or >180°  
Degree of increased hazy attenuation/stranding contact: ≤180° or >180°  
Focal vessel narrowing or contour irregularity: present or absent  
Extension to celiac axis: present or absent  
Extension to bifurcation of right/left hepatic artery: present or absent  
Arterial Variant: Present or absent  
Variant anatomy: Accessory right hepatic artery, replaced right hepatic artery, replaced common 
hepatic artery, others (origin of replaced or accessory artery)  
Variant vessel contact: present or absent  
Degree of solid soft tissue contact: ≤180° or >180° 
Degree of increased hazy attenuation/stranding contact: ≤180° or >180°  
Focal vessel narrowing or contour irregularity: present or absent  
 
Venous evaluation  
MPV: Present, absent, or complete occlusion  
Degree of solid soft tissue contact: ≤180° or >180°  
Degree of increased hazy attenuation/stranding contact: ≤180° or >180°  
Focal vessel narrowing or contour irregularity (tethering or tear drop): present or absent  
SMV: Present, absent, or complete occlusion  
Degree of solid soft- tissue contact: ≤180° or >180°  
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Focal vessel narrowing or contour irregularity (tethering or tear drop): present or absent  
Extension to first draining vein: present or absent  
Thrombus within vein: present or absent (MPV, SMV, or splenic vein) (tumor, bland) 
Venous collaterals: present or absent (around pancreatic head, porta hepatis, root of the mesentery, or 
left upper quadrant)  
 
Extra-pancreatic evaluation  
Liver lesions: present or absent; suspicious/indeterminate or likely benign  
Peritoneal or omental nodules: present or absent  
Ascites: present or absent  
Suspicious lymph nodes: present or absent (porta hepatis, celiac, splenic hilum, paraaortic, 
aortocaval)  
Other extra-pancreatic disease (invasion of adjacent structures): present or absent  
Impression: Tumor: size and location  
Vascular contact: absent or present (vessel involved and extent)  
Metastasis: absent or present (location) 
(Fonseca 2018) 
 
 
 
 
 
 
 
 


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APPENDIX 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
AE Definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to the 
study intervention. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 Any new condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 For situations when an AE or SAE is due to PC report all known signs and symptoms. 
Death due to disease progression in the absence of signs and symptoms should be reported 
as the primary tumor type (e.g., metastatic pancreatic cancer). Note: The term “disease 
progression” should not be used to describe the disease-related event or AE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 


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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
6.1 Results in death 
6.2 Immediately life threatening. 
The term 'life threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
6.3 Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the participant 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 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. 
6.4 Results in persistent disability/incapacity. 
 The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
6.5 Is a congenital anomaly/birth defect 
6.6 Other medically important serious event: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
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Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 All SAEs should be reported within 24 hours of research staff awareness of the event. 
 The investigator will then record all relevant AE/SAE information in the CRF.  
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Galera Therapeutics in lieu of completion of the AE/SAE CRF page. 
 There may be instances when copies of medical records for certain cases are requested by 
Galera Therapeutics. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Galera Therapeutics. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 The investigator must assign the following AE attributes: 
o AE diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Intensity (or toxicity defined below); 
o Assessment of relatedness to GC4711, SBRT; and 
o Action taken. 
Assessment of Intensity/Grade 
The investigator will assess intensity for each AE and SAE reported during the study and 
assign a grade per NCI CTCAE vs. 5.0. For those AEs not directly referenced in CTCAE, the 
investigator should use clinical judgment in assessing the intensity of such events using the 
categories below as a guide 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 Life Threatening: an event that in the view of either the investigator or sponsor, its 
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 Fatal: an event resulting in death 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. The greatest intensity 
during a continuous episode should be recorded. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Galera Therapeutics. However, it is very 
important that the investigator always assesses causality for every event before the 
initial transmission of the SAE data to Galera Therapeutics. 
 The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Galera 
Therapeutics to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 New or updated information will be recorded in the originally completed CRF. 
 The investigator will submit any updated SAE data to Galera Therapeutics within 24 hours 
of receipt of the information. 


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Reporting of SAEs 
SAE Reporting to Galera Therapeutics  
The SAE/AESI reporting period begins from the Day 1 dosing of study drug. SAEs will be 
reported until 90 days post-SBRT. 
Within 24 hours of knowledge of a new SAE, the Investigator must report the event on a 
Safety Event Report Form to Propharma Safety Management or risk a major protocol 
deviation. The SAE report may be faxed, phoned or emailed to Propharma Safety 
Management. A phoned SAE report must be followed by a written report as soon as 
possible.  
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent). 
 
 
 


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APPENDIX 5: NCCN Guidelines v1.2020- Criteria Defining Locally advanced  
Versus Borderline Resectable PC 
 
 


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APPENDIX 6: PRO-CTCAE 
See Basch 2014, Kluetz 2016.  
 


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APPENDIX 7: Multidisciplinary Review Worksheets 
 


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APPENDIX 8: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions: 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
 Premenarchal 
 Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
 Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
Effective Methods of Contraception 
 A highly effective method of contraceptive is defined as any methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly are considered as 
highly effective birth control methods.   
 Such methods include:  
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:  
o oral  
o intravaginal  
o transdermal  
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o oral  
o injectable  
o implantable   
 intrauterine device (IUD)  
 intrauterine hormone-releasing system (IUS)  
 bilateral tubal occlusion  
 vasectomized partner  
 sexual abstinence   
 
Male participants with partners who become pregnant 
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive GC4711. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.  
Female Participants who become pregnant/breastfeed 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant or breastfeeds during treatment and 30 days after GC4711/placebo. Information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring at > 22 
weeks gestational age) is always considered to be an SAE and will be reported as such.  
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. 


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APPENDIX 9: Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
Activated partial thrombin time 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
Area under the curve 
BED 
biologically equivalent dose 
BMI 
body mass index  
BP  
blood pressure 
BUN 
blood urea nitrogen  
CBC 
complete blood count 
CFR 
Code of Federal Regulation 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences  
CONSORT 
Consolidated Standards of Reporting Trials  
CRF 
Case Report Form 
CSR 
Clinical Study Report  
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
CTV 
Clinical target volume 
DFS 
disease free survival 
DMC 
Data Monitoring Committee  
DRE 
disease related event 
E/D  
early discontinuation 
ECG 
electrocardiogram 
ECOG PS 
eastern cooperative oncology group performance status 
eCRF 
electronic Case Report Form 
5FU 
F – fluorouracil 
FDA 
Food and Drug Administration 


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FOLFIRINOX 
Chemotherapy combination of cancer drugs that includes: FOL – folinic acid 
(also called leucovorin, calcium folinate or FA) F – fluorouracil (also called 
5FU) Irin – irinotecanand Ox – oxaliplatin. 
(m)FOLFIRINOX 
modified FOLFIRINOX, no bolus given 
FOLFOX 
Chemotherapy combination of cancer drugs that includes: FOL – folinic acid 
(also called leucovorin, calcium folinate or FA) F – fluorouracil (also called 
5FU) and Ox – oxaliplatin 
FOLFIRI 
Chemotherapy combination of cancer drugs that includes: FOL – folinic acid 
(also called leucovorin, calcium folinate or FA) F – fluorouracil (also called 
5FU) and Iri – irinotecan 
FSH 
follicle stimulating hormone  
FU 
follow-up 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice  
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GTV 
Gross tumor volume 
Gy 
Gray 
hCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy  
IB 
Investigator’s Brochure  
ICF 
Informed Consent Form  
ICH  
International Council for/Conference on Harmonisation 
IEC 
Independent Ethics Committees  
IMRT 
Intensity modulated radiation therapy 
INR 
International normalized ratio 
IRB 
Institutional Review Boards  
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
IXRS 
interactive voice or web-based randomization system 
LC-MS 
liquid chromatography – mass spectrometry  


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LD 
largest tumor diameter 
LE 
local enlargement 
LRC 
Local regional control 
MDSCs 
myeloid-derived suppressor cells 
MRI 
Magnetic resonance imaging 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
NCCN 
National comprehensive cancer network 
NSCLC 
Non-small lung cancer 
NK cells 
natural killer cells 
NMR 
nuclear magnetic resonance 
NOAEL 
no observed adverse effect level 
OAR 
Organs at risk 
OS 
overall survival 
PC 
Pancreatic cancer 
PDE 5 
phosphodiesterase type 5 
PE 
physical examination 
PET 
FDG-positron emission tomography 
PFS 
progression-free survival 
PK 
Pharmacokinetic(s)  
PT 
Prothrombin time 
PTV 
planning target volume 
RBC 
red blood cell  
RECIST 
response evaluation criteria in solid tumors 
RNA 
ribonucleic acid  
RT 
radiation therapy 
RTOG 
radiation therapy oncology group 
RTQA 
radiation therapy quality assurance 
RT-qPCR 
reverse transcriptase polymerase chain reaction 
RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event  


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SABR 
stereotactic ablative body radiation therapy 
SBRT 
stereotactic body radiation therapy 
SGOT 
serum glutamic-oxaloacetic transaminase  
SGPT 
serum glutamic-pyruvic transaminase  
SOA  
schedule of assessments 
SOD 
superoxide dismutase 
SRC 
safety review committee 
SUSAR 
suspected unexpected serious adverse reactions 
TCD 
tumor cure dose 
TDM 
Time to distant metastases 
TEAEs 
Treatment emergent adverse events 
Tregs 
T regulatory cells 
ULN 
upper normal limit 
WBC 
white blood cell  
WOCBP 
woman of childbearing potential  
 
 
 


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12 SUMMARY OF CHANGES 
Revisions made in Amendment 6 dated 08 October 2023 are summarized below: 
Summary of Change  
Rationale  
Affected Protocol 
Sections 
Added an interim test of 
superiority at 
approximately 36 deaths 
The addition of an interim efficacy analysis by the 
DMC at approximately 36 events (i.e., deaths) has 
been added to the protocol to determine if the 
clinical trial is on track to meet its objective of 
demonstrating an improvement in overall survival. 
With the current standard of care for the treatment 
of locally advanced pancreatic cancer, subjects are 
living longer and therefore the number of events 
required to perform the previously defined interim 
analysis for superiority is taking longer to meet 
than anticipated. This additional analysis, blinded 
to Sponsor unless the DMC recommends stopping 
the trial for futility, will assess the likelihood of 
demonstrating statistical superiority of study drug 
if the trial continues to full enrollment and follow 
up, and allow a decision to be made regarding 
further patient enrollment. 
· Synopsis 
· Section 9  
Administrative, Clerical 
and Formatting updates 
Revised to permit better readability.  
· Overall 
Protocol