Conditions: Radiation Induced Oral Mucositis
Keywords: squamous cell carcinoma of the head and neck oral cavity oropharynx intensity-modulated radiation therapy chemotherapy oral mucositis superoxide dismutase radioprotection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 223
Healthy volunteers: no

Brief summary:
The purpose of the phase 2, GT-201 clinical study is to determine if GC4419 administered prior to intensity-modulated radiation therapy (IMRT) reduces the incidence, duration, and severity of radiation induced oral mucositis in patients who have been diagnosed with locally advanced, non-metastatic squamous cell carcinoma of the head and neck.

Detailed description:
GT-201 is a randomized, double-blind, placebo-controlled, multi-center study conducted in the U.S. to evaluate GC4419 administered via an intravenous line (IV) for the reduction of incidence, duration, and severity of radiation induced oral mucositis in patients receiving cisplatin plus intensity-modulated radiation therapy for post-operative, or definitive treatment of locally advanced, non-metastatic squamous cell carcinoma of the head and neck, limited to the oral cavity or oropharynx. Patients will be randomized equally to 1 of 3 treatment arms:

Arm A: 30 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Arm B: 90 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Arm C: Placebo daily (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Planned radiation fields in all 3 arms must include at least two oral sites (buccal mucosa, floor of mouth, tongue, soft palate) with each site receiving a dose of at least 50 Gy.

All patients will be assessed twice weekly for oral mucositis per WHO grading criteria until the completion of IMRT, and once weekly thereafter (if necessary) for 8 weeks, or until oral mucositis resolves to ≤ Grade 1.

Approximately 200 total to ensure that roughly 60 patients per arm receive study drug and complete requirements for primary endpoint analysis, which is defined as patients receiving a minimum cumulative dose of 60 Gy.

Arms:
arm 1: 30 mg GC4419/day prior to IMRT arm 2: 90 mg GC4419/day prior to IMRT arm 3: Placebo daily, prior to IMRT

Interventions: intervention 1: Low Dose GC4419: 30mg/day intervention 2: High Dose GC4419: 90mg/day intervention 3: Placebo intervention 4: Intensity-Modulated Radiation Therapy intervention 5: Cisplatin
Intervention descriptions: intervention 1: Low Dose GC4419 will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks). intervention 2: High Dose GC4419 will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks). intervention 3: Placebo will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks). intervention 4: Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks intervention 5: Administered 80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses.

Substitution of other systemic agents due to related toxicities (i.e., carboplatin) would be evaluated to determine eligibility by the Medical Monitor

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol GT-201 
Galera Therapeutics, Inc. 
Confidential 
   Amendment 6 
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1.
TITLE PAGE
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center, Trial of the Effects of Intravenous GC4419 on the 
Incidence and Duration of Severe Oral Mucositis (OM) in Patients 
Receiving Post-Operative or Definitive Therapy with Single-Agent 
Cisplatin plus IMRT for Locally Advanced, Non-Metastatic 
Squamous Cell Carcinoma of the Oral Cavity or Oropharynx 
Sponsor: 
Galera Therapeutics, Inc. 
IND Number: 
111,539 
Protocol ID: 
GT-201 
Medical Monitor: 
Jon T. Holmlund, MD  
Protocol Version/Date: 
Amendment 6: 19 October 2017 
CONFIDENTIAL INFORMATION 
The information contained in this document is proprietary to Galera Therapeutics, Inc.  The 
information is to be used only in connection with review of, or participation in, authorized 
clinical studies of the investigational drug described in the protocol.   Disclosure of the 
information to others not under obligations to maintain this information in confidence is 
prohibited without written authorization from Galera Therapeutics, Inc. with the exception that, to 
the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered, a general protocol description may be disclosed to such potential patients. 
NCT02508389




Clinical Study Protocol GT-201 
 
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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Galera Therapeutics, Inc. 
Name of Investigational Product: 
GC4419 
Name of Active Ingredient: 
GC4419 (Manganese, dichloro[(4aS,13aS,17aS,21aS)-
1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-11,7- nitrilo-7H- 
dibenzo[b,h][1,4,7,10] tetraazacycloheptadecine-κN5, κN13, κN18, κN21, κN22]-) is a water soluble, 
highly stable, low molecular weight manganese-containing macrocyclic ligand complex whose 
activity mimics that of naturally occurring SOD enzymes. 
Title of Study:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial of the Effects of 
Intravenous GC4419 on the Incidence and Duration of Severe Oral Mucositis (OM) in Patients 
Receiving Post-Operative or Definitive Therapy with Single-Agent Cisplatin plus IMRT for Locally 
Advanced, Non-Metastatic Squamous Cell Carcinoma of the Oral Cavity or Oropharynx 
Number of Study Center(s): Approximately 60 sites in the United States and approximately 5 sites 
in Canada. 
Estimated Enrollment Period: 22 months 
Studied period (years):  
Estimated date first patient enrolled: October 2015 
Estimated date last patient completed Active Phase: July 2017 
Phase of development: 2 
 
Objectives:  
Primary: 
• 
To evaluate and compare the duration of severe OM, as assessed from the first 
determination of ≥ Grade 3 OM to the first instance of non-severe OM (≤ Grade 2), 
without a subsequent instance of ≥ Grade 3 
Secondary: 
• 
To evaluate and compare the safety of GC4419 at the treatment assignment of each 
respective arm   
• 
To evaluate and compare the effects of GC4419, administered at each of two daily doses 
vs. placebo, on the cumulative incidence of severe OM, defined as any occurrence of 
WHO Grade 3-4 OM, from the first IMRT fraction through the delivery of the 30th IMRT 
fraction (approximately 60 Gy delivered to tumor) 
• 
To evaluate and compare the cumulative incidence of severe OM from the first IMRT 
fraction through the last IMRT fraction   
• 
To evaluate and compare the cumulative incidence of Grade 4 OM from the first IMRT 
fraction through the last IMRT fraction  


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• 
To evaluate and compare the onset of severe OM expressed as the number of IMRT 
fractions delivered at onset of severe OM 
• 
To evaluate and compare the effect of treatment assignment on tumor outcomes 
(locoregional failure, distant metastases, progression-free survival, overall survival) 
Exploratory: 
• 
To evaluate and compare duration of severe OM among subjects with severe OM 
• 
To evaluate and compare the time to onset of severe OM: expressed both as cumulative 
IMRT dosage delivered and as time (days) at onset of severe OM 
• 
To evaluate and compare the time to onset of severe OM among subjects with severe 
OM: time (days), cumulative IMRT dosage, and number of IMRT fractions delivered at 
onset of severe OM 
• 
To evaluate and compare the duration of severe OM, as assessed by the number of 
instances of severe OM of ≥ 7 days’ duration, defined as severe OM recorded at two or 
more consecutive OM evaluations  
• 
To evaluate and compare severe OM incidence from the first IMRT fraction through the 
end of post-IMRT early follow-up; post-IMRT early follow-up will extend for up to 8 
weeks post the last IMRT fraction administered or until a given patient’s OM is WHO 
Grade 0 or 1   
• 
To evaluate and compare cumulative severe OM incidence at cumulative delivery of 20-
29, 30-39, 40-49, or 50-59 Gy of IMRT 
• 
To evaluate and compare the duration of Grade 4 OM from the first IMRT fraction 
through the last IMRT fraction 
• 
To evaluate and compare the areas under the OM-severity vs. cumulative IMRT dosage 
curves 
• 
To evaluate and compare the number and percentage of patients with severe OM on more 
than one visit prior to Week 6, Visit 2 
• 
To evaluate and compare the total number of assessments (per patient) of severe OM 
through the end of IMRT 
• 
To evaluate and compare the effects of GC4419 on the incidence, onset, and duration of 
ulcerative (≥ Grade 2) OM 
• 
To evaluate and compare treatment delivery and delays (number and duration of delays) 
of IMRT and cisplatin 
• 
To evaluate and compare the effects of GC4419 on other specific toxicities of interest 
associated with concurrent chemoradiation:  xerostomia, trismus, fatigue, weight loss, 
radiation dermatitis, and dysgeusia (changes in taste) 
• 
To evaluate and compare the effects of treatment on patient-reported outcomes as 
obtained using the Oral Mucositis Daily Questionnaire (OMDQ) 


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• 
To evaluate and compare the use of narcotic analgesics by patients according to treatment 
assignment 
• 
To evaluate and compare frequency, use, and reasons for use of gastrostomy tubes  
• 
To evaluate and compare the use and complications of indwelling venous access devices 
• 
To evaluate and compare the frequency and reasons for unscheduled hospitalizations 
• 
To assess the effects of treatment assignment on circulating cytokine levels and gene 
expression levels 
Methodology:  
GT-201 is a randomized, double-blind, placebo-controlled, multi-center study conducted in the U.S. 
to evaluate GC4419 administered IV to reduce the duration, incidence, and severity of radiation 
induced oral mucositis in patients receiving chemoradiation for SCCHN, limited to the oral cavity or 
oropharynx.  Patients will be randomized equally to 1 of 3 treatment arms:  
• 
Arm A: 30 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior 
to IMRT), concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy 
over approximately 7 weeks, plus cisplatin administered 80-100 mg/m2 once every three 
weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses (investigator’s choice) 
• 
Arm B: 90 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior 
to IMRT), concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy 
over approximately 7 weeks, plus cisplatin administered 80-100 mg/m2 once every three 
weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses (investigator’s choice) 
• 
Arm C:  Placebo daily (60 min IV infusion to complete within 60 minutes prior to 
IMRT), concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over 
approximately 7 weeks, plus cisplatin administered 80-100 mg/m2 once every three 
weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses (investigator’s choice) 
Note: Planned radiation fields in all 3 arms must include at least 2 oral sites (buccal mucosa, floor of 
mouth, tongue, soft palate) with each site receiving a dose of at least 50 Gy. 
All patients will be assessed twice weekly for oral mucositis per WHO grading criteria until the 
completion of IMRT, and once weekly thereafter (if necessary) for 8 weeks, or until oral mucositis 
resolves to ≤ Grade 1.  Sparse PK sampling will be sought from all patients. 
Number of patients (planned):  
Approximately 216 total to ensure that roughly 65 patients per arm receive study drug and complete 
their IMRT course, with an assumed proportion of early discontinuations of 10%.  
Diagnosis and main criteria for inclusion:  
Inclusion Criteria:  
1. Pathologically-confirmed diagnosis of squamous cell carcinoma of the head and neck, 
defined as SCC of the oral cavity or oropharynx that will be treated with cisplatin plus 
concurrent IMRT 


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Note: Patients with unknown primary tumors whose treatment plan matches the requirements 
specified in Inclusion Criteria #2 and #3 below are eligible for the trial.   
2. Treatment plan to receive a continuous course of IMRT delivered as single daily fractions of 
2.0 to 2.2 Gy with a cumulative radiation dose between 60 Gy and 72 Gy. Planned radiation 
treatment fields must include at least two oral sites (buccal mucosa, floor of mouth, tongue, 
soft palate) that are each planned to receive a total of ≥ 50 Gy. Patients who have had prior 
surgery are eligible, provided they have fully recovered from surgery, and patients who may 
have surgery in the future are eligible. 
Note: Unavoidable doses of at least 50 Gy, to include entrance, exit, and scatter doses, still 
constitutes planned radiation. 
3. Treatment plan to receive standard cisplatin monotherapy administered either every three 
weeks (80-100 mg/m2 for 3 doses) or weekly (30-40 mg/m2 for 6-7 doses). The decision on 
which cisplatin regimen to use in combination with IMRT and GC4419 will be at the 
discretion of the investigator. 
4. Age 18 years or older 
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2  
6. Adequate hematologic function as indicated by: 
• 
Absolute neutrophil counts (ANC) ≥ 1,500/mm3 
• 
Hemoglobin (Hgb) ≥ 9.0 g/dL 
• 
Platelet count ≥ 100,000/mm3 
7. Adequate renal and liver function as indicated by: 
• 
Serum creatinine acceptable for treatment with cisplatin per institutional guidelines 
• 
Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
• 
Alkaline phosphatase ≤ 2.5 x ULN  
8. Human papilloma virus (HPV) status in tumor has been documented using tumor 
immunohistochemistry for HPV-p16 or other accepted test 
9. Serum pregnancy test negative for females of childbearing potential 
10. Males and females must agree to use effective contraception starting prior to the first day of 
treatment and continuing for 30 days after the last dose of GC4419 
11. Properly obtained written informed consent 
Exclusion Criteria: 
1. Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands 
2. Metastatic disease (Stage IV C) 
3. Prior radiotherapy to the region of the study cancer or adjacent anatomical sites or more than 
25% of total body marrow-bearing area (potentially interfering with chemo-tolerance) 


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4. Prior induction chemotherapy 
5. Receiving any approved or investigational anti-cancer agent other than those provided for in 
this study 
6. Concurrent participation in another interventional clinical trial or use of another 
investigational agent within 30 days of study entry 
Note: Patients who are participating in non-interventional clinical trials (e.g., QOL, imaging, 
observational, follow-up studies, etc.) are eligible, regardless of the timing of participation. 
7. Requirement for significantly modified diet (liquids and/or nothing by mouth) due to 
compromised oral/pharyngeal function at baseline 
8. Complete reliance on parenteral or gastrointestinal tube-delivered nutrition at baseline  
Note: Patients who have gastrostomy tubes prophylactically placed are eligible. Patients 
receiving supplemental nutrition through a gastrostomy tube at baseline may be eligible 
depending on diet. 
9. Malignant tumors other than HNC within the last 5 years, unless treated definitively and with 
low risk of recurrence in the judgment of the treating investigator  
10. Active infectious disease excluding oral candidiasis 
11. Presence of oral mucositis (WHO Score ≥ Grade 1) at study entry 
12. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for 
hepatitis B and do not have a history of infection are eligible) 
13. Female patients who are pregnant or breastfeeding 
14. Known allergies or intolerance to cisplatin and similar platinum-containing compounds 
15. Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment 
of the treating investigator, create a risk for a precipitous decrease in blood pressure. 
16. Medical history that includes any condition, or requires the use of concomitant medications 
which, in the investigator’s judgment, are associated with or create a risk of increased carotid 
sinus sensitivity, symptomatic bradycardia, or syncopal episodes.   
Investigational product, dosage and mode of administration:  
GC4419 is formulated as a clear solution at a concentration of 3 mg/mL or 9 mg/mL (Arm A [30mg] 
and B [90mg], respectively) in 26 mM sodium bicarbonate-buffered 0.9 wt. % saline for parenteral 
administration (drug product).  GC4419 will be presented in 35 single use amber vials, one vial per 
day.  Vials will be filled with 11 mL of GC4419, of which 10 mL be added into a 250 mL bag of 
normal saline, for daily IV administration over 60 minutes.  GC4419 will be administered concurrent 
with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over 7 weeks, plus cisplatin 
administered 80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 
doses (investigator’s choice). 
 


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Duration of treatment:  
Approximately 35 doses, on days in which IMRT is administered, Monday-Friday, for approximately 
7 weeks.  GC4419 will be administered within 1 hour prior to each IMRT treatment. 
Reference therapy, dosage and mode of administration:  
Placebo will consist of 26 mM sodium bicarbonate-buffered 0.9 wt. % saline for parenteral 
administration only (Arm C). Placebo will be presented in 35 single use amber vials, one vial per day.  
Vials will be filled with 11 mL of placebo, of which 10 mL be added into a 250 mL bag of normal 
saline, for daily IV administration over 60 minutes.  Placebo will be administered concurrent with 
daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over 7 weeks, plus cisplatin administered 
80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses 
(investigator’s choice).   
Clinical Laboratory Assessment: A central laboratory vendor will be utilized. 
Criteria for evaluation: 
Efficacy: 
• 
World Health Organization (WHO) Criteria for Oral Mucositis 
Safety: 
• 
National Cancer Institute - Common Terminology Criteria for Adverse Events, version 
4.03 
Patient-Reported Outcomes:   
• 
Oral Mucositis Daily Questionnaire 
• 
Visual Analogue Scale of Xerostomia 
Safety Monitoring and Toxicity Management: 
1. Adverse/Serious Adverse Event assessments per CTCAE version 4.03 and GCP standards  
2. Safety will be monitored by a Data Monitoring Committee. 
3. Toxicity requiring 25% GC4419 or PBO dose reduction: 
• 
Grade 3 flushing 
• 
Grade 2 or greater hypotension within 2 hours after the start of GC4419/placebo infusion 
• 
Grade 3 or 4 infusion reaction with GC4419/placebo 
• 
Grade 4 vomiting despite optimal antiemetic therapy per current ASCO and MASCC 
guidelines  
Two dose reductions for toxicity will be permitted per patient. Patients unable to tolerate 
GC4419/placebo after two dose reductions must discontinue treatment with the study drug GC4419 
but may continue with cisplatin/IMRT at the discretion of the treating investigator. 


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For other toxicities (including those attributable to cisplatin and IMRT): management per institutional 
and ASCO guidelines and investigator judgment.  Cisplatin toxicities should be managed by 
modification of the cisplatin dose and schedule, not by substitution of another systemic agent. 
OM and xerostomia will NOT be considered adverse events requiring dose modification for the 
purposes of this study. 
Concomitant Medications/Treatments: 
Investigators may prescribe any concomitant medication or supportive therapy deemed necessary to 
provide adequate supportive care including antiemetics, systemic antibiotics, hydration to prevent 
renal damage, topical fluoride etc., with the following exceptions:  
 Low-level laser treatment for OM 
 Amifostine (Ethyol®)   
 Benzydamine (Difflam®) 
 Cetuximab (Erbitux®)  
 Glutamine applied topically  
 GM-CSF applied topically  
 ‘Magic mouthwashes’ or ‘Miracle mouthwashes’ are permitted, provided they do not 
contain:  
 Chlorhexidine  
 Hydrogen peroxide  
 Diphenhydramine (Benadryl®)  
 Tetracycline  
 Any other listed disallowed medications  
 Notes:  
o Topical lidocaine preparations are permitted 
o Diphenhydramine (Benadryl®) administered as tablets for by injection is 
permitted; only diphenhydramine liquid formulation is prohibited 
 MuGard™, Gelclair®, Episil®, or other barrier devices 
 Caphosol® 
 Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildanefil, tadalafil, or similar 
agents) or other drugs that in the judgment of the treating investigator could create a risk of 
a precipitous decrease in blood pressure are prohibited until at least 24 hours after the last 
dose of GC4419 
 Pyridostigmine or other drugs that in the judgment of the treating investigator could create 
a risk of increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal 
episodes.  


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 Palifermin (Kepivance®) or other keratinocyte or fibroblast growth factor  
 Povidone-iodine rinses  
 Steroid rinses  
 Sucralfate in suspension form (use of sucralfate tablets is not proscribed)  
 Other biologic response modifiers – except systemic hematopoietic growth factors for the 
management of anemia or myelosuppression  
 Concurrent approved or investigational anti-cancer therapy (e.g., chemotherapy, 
immunotherapy, targeted therapy, hormone and biologic therapy) other than the Protocol 
regimen  
 Other investigational agents 
All medication restrictions end after post-IMRT OM follow-up is completed unless otherwise noted. 
Anti-emetic prophylaxis and hematopoietic growth factor use are permitted per ASCO guidelines.  
Following ASCO (and MASCC) guidelines for the prevention and management of chemotherapy-
induced nausea and vomiting (CINV) is strongly encouraged. 
Statistical methods: 
With 65 patients per arm having received GC4419/placebo and completed their IMRT course 
(assumes 72 patients enrolled to each treatment arm with a 10% dropout rate), the study will have 
roughly 80-85% power to detect a reduction in duration in the experimental arm under the following 
assumed incidence of severe OM and percentiles of the distribution of duration of severe OM: 
• 
GC4419 arms: incidence = 40%; duration (25th, 50th, 75th percentile): 0, 0, 21 days  
• 
Control arm: incidence = 65%; duration (25th, 50th, 75th percentile): 0, 28, 50 days 
For each active dose, duration of severe OM will be compared to the placebo duration using the van 
Elteren test stratified by the factors used in randomization, namely baseline HPV status and planned 
chemotherapy schedule. 
To control the overall 2-sided Type I error rate of 0.05, testing of hypotheses for the primary and 
secondary endpoints will follow a fixed sequence, continuing until a preceding hypothesis fails to be 
rejected at the 0.05 level.    
Additional details will be provided in the Statistical Analysis Plan.  In the event of discrepancies of 
details between the protocol and the Statistical Analysis Plan, the latter will control the analyses 
performed. 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
4. 
INTRODUCTION ......................................................................................................21 
4.1. 
Background .................................................................................................................21 
4.1.1. 
Oral Mucositis in Patients Treated with Chemoradiation for HNC ...........................21 
4.1.2. 
Oral Mucositis is an Unmet Medical Need.................................................................23 
4.2. 
GC4419 .......................................................................................................................23 
4.2.1. 
Biological Rationale for GC4419 in Radiation/Chemotherapy Induced OM ............24 
4.3. 
Pre-Clinical GC4419 Data ..........................................................................................25 
4.3.1. 
Pre-Clinical Data with GC4419 in Hamster Models for Radiation-Induced 
OM ..............................................................................................................................25 
4.3.2. 
GC4419 is not Tumor Protective in Non-Clinical Cancer Models. ............................25 
4.4. 
Phase I Study of GC4419, GT-001 .............................................................................26 
4.4.1. 
Clinical Data with GC4419 in Radiation/Chemotherapy Induced OM ......................26 
4.4.2. 
Oral Mucositis Clinical Data from GT-001 ................................................................27 
4.4.3. 
Clinical Safety Data with GC4419 .............................................................................32 
4.5. 
Randomized Phase II Study of GC4419, GT-201 ......................................................34 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................35 
5.1. 
Primary Objective .......................................................................................................35 
5.1.1. 
Rationale for Primary Endpoint ..................................................................................35 
5.2. 
Secondary Objectives .................................................................................................36 
5.3. 
Exploratory Objectives ...............................................................................................36 
6. 
INVESTIGATIONAL PLAN .....................................................................................39 
6.1. 
Overall Study Design ..................................................................................................39 
6.2. 
Treatment Plan and Duration of Therapy ...................................................................39 
6.2.1. 
Rationale for GC4419 Dose and Schedule Selection .................................................40 
6.2.2. 
Rationale for Cisplatin/IMRT Treatment Plan ...........................................................40 
6.2.3. 
Rationale for Tumor Follow-up and Analysis ............................................................41 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................43 
7.1. 
Subject Inclusion Criteria ...........................................................................................43 
7.2. 
Subject Exclusion Criteria ..........................................................................................44 
7.3. 
Rationale for Patient Population .................................................................................45 
7.4. 
Screen Failures ............................................................................................................45 
7.5. 
Randomization Failures ..............................................................................................45 
7.6. 
Subject Withdrawal Criteria .......................................................................................46 
7.7. 
Study and Site Closure................................................................................................46 
8. 
TREATMENT OF SUBJECTS ..................................................................................48 
8.1. 
Concomitant Medications ...........................................................................................48 
8.1.1. 
Prohibited Medications ...............................................................................................48 
8.2. 
Treatment Compliance ................................................................................................50 
8.3. 
Randomization and Blinding ......................................................................................50 
8.3.1. 
Treatment Assignment ................................................................................................50 
8.3.2. 
Stratification ...............................................................................................................50 
8.3.3. 
Blinding ......................................................................................................................50 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
9.1. 
Description of Study Drug ..........................................................................................51 
9.2. 
Study Drug Packaging and Labeling ..........................................................................51 
9.3. 
GC4419 .......................................................................................................................51 
9.4. 
Placebo ........................................................................................................................51 
9.5. 
Study Drug Storage .....................................................................................................52 
9.6. 
Study Drug Preparation ..............................................................................................52 
9.7. 
Administration ............................................................................................................52 
9.8. 
Study Drug Accountability .........................................................................................54 
9.9. 
Study Drug Handling and Disposal ............................................................................55 
10. 
TOXICITY MANAGEMENT ....................................................................................56 
10.1. 
Dose Delays and Dose Modifications for Toxicity ....................................................56 
10.2. 
Supportive Care Guidelines ........................................................................................56 
10.2.1. 
Supportive care for chemotherapy-induced nausea and vomiting (CINV) ................56 
11. 
ASSESSMENTS.........................................................................................................57 
11.1. 
Safety Assessments .....................................................................................................57 
11.1.1. 
Clinical Assessments ..................................................................................................57 


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11.1.2. 
Laboratory Assessments .............................................................................................57 
11.2. 
Oral Mucositis Assessments .......................................................................................58 
11.3. 
Radiation Therapy Quality Assurance ........................................................................58 
11.4. 
Patient Reported Outcomes (PRO) .............................................................................59 
11.4.1. 
Oral Mucositis Daily Questionnaire (OMDQ) ...........................................................59 
11.5. 
Health and Economic Outcomes ................................................................................59 
11.5.1. 
Pain Medication Diary ................................................................................................60 
11.6. 
Pharmacokinetic (PK) Measurements ........................................................................60 
11.7. 
Biological Surrogate Markers of Mucositis ................................................................61 
11.8. 
Tumor Status Assessment ...........................................................................................61 
11.8.1. 
Clinical Tumor Assessment ........................................................................................61 
11.8.2. 
Tumor Imaging ...........................................................................................................62 
11.8.2.1. 
Pre-Treatment Tumor Imaging ...................................................................................62 
11.8.2.2. 
Post-Treatment Tumor Imaging .................................................................................62 
11.9. 
Xerostomia and Trismus Assessments .......................................................................62 
11.10. 
Schedule of Time and Events .....................................................................................63 
11.11. 
Screening Phase ..........................................................................................................63 
11.12. 
Active Phase ...............................................................................................................64 
11.12.1. 
Baseline/Day 1 (First Day of IMRT and GC4419) ....................................................64 
11.12.2. 
Day 2 of IMRT and GC4419 ......................................................................................65 
11.12.3. 
Days 3 to 5 of IMRT and GC4419 .............................................................................65 
11.12.4. 
Week 2 ........................................................................................................................65 
11.12.5. 
Week 3 ........................................................................................................................66 
11.12.6. 
Week 4 ........................................................................................................................67 
11.12.7. 
Week 5 ........................................................................................................................68 
11.12.8. 
Week 6 ........................................................................................................................69 
11.12.9. 
Week 7 (plus additional IMRT weeks, if needed) ......................................................69 
11.12.10. 
Last Day of IMRT or Early Termination Visit ...........................................................70 
11.12.11. 
Post-IMRT Weeks 1 through 8 ...................................................................................71 
11.13. 
Post-Active Phase .......................................................................................................71 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................72 
12.1. 
Definitions ..................................................................................................................72 
12.1.1. 
Adverse Event (AE) ....................................................................................................72 


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12.1.2. 
Serious Adverse Event (SAE) ....................................................................................72 
12.2. 
Adverse Event Reporting Requirements ....................................................................73 
12.2.1. 
Serious Adverse Events ..............................................................................................73 
12.2.2. 
All Adverse Events (AEs) Regardless of Seriousness ................................................73 
12.2.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs ....................................................................................................................73 
12.2.4. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs ...........................................................................................................................74 
12.2.5. 
Grading of Adverse Events .........................................................................................74 
12.3. 
Relationship to Study Drug ........................................................................................75 
12.4. 
Follow-up of AEs and SAEs .......................................................................................75 
12.5. 
Post-Study Reporting Requirements ...........................................................................76 
12.6. 
Pregnancy ...................................................................................................................76 
12.6.1. 
Time Period for Collecting Pregnancy Information ...................................................76 
12.6.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male 
Patient .........................................................................................................................76 
12.7. 
Recording Adverse Events .........................................................................................77 
12.8. 
Regulatory Reporting of Adverse Events ...................................................................77 
13. 
STATISTICS ..............................................................................................................79 
13.1. 
General Considerations ...............................................................................................79 
13.1.1. 
Randomization and Stratification ...............................................................................79 
13.2. 
Sample Size ................................................................................................................79 
13.3. 
Analysis Populations ..................................................................................................80 
13.4. 
Definition of Endpoints ..............................................................................................80 
13.4.1. 
Primary Endpoint ........................................................................................................80 
13.4.2. 
Secondary Endpoints ..................................................................................................80 
13.4.3. 
Exploratory Endpoints ................................................................................................81 
13.5. 
Safety Analysis ...........................................................................................................82 
13.6. 
Primary Efficacy Analysis ..........................................................................................82 
13.6.1. 
Multiplicity .................................................................................................................82 
13.6.2. 
Handling of Missing Data ...........................................................................................83 
13.6.3. 
Covariate Adjustment .................................................................................................83 
13.7. 
Secondary Efficacy Analyses .....................................................................................84 


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13.7.1. 
Cumulative Incidence Endpoints ................................................................................84 
13.7.2. 
Onset of Severe OM: Number of IMRT Fractions Delivered at Onset of 
Severe OM, Time (days), and Cumulative IMRT Delivered at Onset of 
Severe OM ..................................................................................................................84 
13.8. 
Exploratory Efficacy Analyses ...................................................................................84 
13.8.1. 
Instances of severe OM lasting ≥ 7 days ....................................................................84 
13.9. 
Analysis of Tumor Endpoints .....................................................................................84 
13.9.1. 
Local or Regional Progression....................................................................................84 
13.9.2. 
Distant Metastasis .......................................................................................................84 
13.9.3. 
Second Primary Neoplasm .........................................................................................85 
13.10. 
Data Monitoring Committee (DMC) ..........................................................................85 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................86 
14.1. 
Study Monitoring ........................................................................................................86 
14.2. 
Audits and Inspections ................................................................................................86 
14.3. 
Protocol Compliance ..................................................................................................87 
14.4. 
Protocol Modifications ...............................................................................................87 
14.5. 
Information Disclosure ...............................................................................................87 
14.5.1. 
Ownership ...................................................................................................................87 
14.5.2. 
Confidentiality ............................................................................................................87 
14.5.3. 
Publication ..................................................................................................................87 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................88 
16. 
ETHICS ......................................................................................................................89 
16.1. 
Ethical Conduct of the Study ......................................................................................89 
16.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval ..........................................................89 
16.3. 
Written Informed Consent ..........................................................................................89 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................90 
17.1. 
Case Report Forms .....................................................................................................90 
17.2. 
Retention/Inspection of Records.................................................................................90 
18. 
LIST OF REFERENCES ............................................................................................91 
19. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ....................................................95 
20. 
APPENDIX 2: WHO SCORE ....................................................................................98 
21. 
APPENDIX 3: ORAL MUCOSITIS DAILY QUESTIONNAIRE ...........................99 


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22. 
APPENDIX 4: PERFORMANCE STATUS CONVERSION .................................100 
23. 
APPENDIX 5: NATIONAL CANCER INSTITUTE-COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS, VERSION 4 ...............101 
24. 
APPENDIX 6: XEROSTOMIA ASSESSMENT (LEVEQUE, 1993) .....................102 
25. 
APPENDIX 7.  RECOMMENDED REGIMENS FOR HIGH-RISK 
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV) PER 
ASCO AND MASCC GUIDELINES ......................................................................103 
26. 
APPENDIX 8: SUMMARY OF CHANGES IN AMENDMENT 6........................105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Tables 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 2: 
Cumulative Onset of WHO Grade 3-4 OM vs. Total IMRT in Patients 
Receiving Concurrent Single-Agent Cisplatin ...........................................................22 
Table 3: 
GT-001 Enrollment .....................................................................................................27 
Table 4: 
Cumulative Onset of WHO Grade 3-4 OM vs. Total IMRT in GT-001, 
Compared with Unpublished Experience from S. Sonis ............................................28 
Table 5: 
OM parameters for GC4419 (GT-001 trial) compared with historical 
matched and published control data ...........................................................................32 
Table 6: 
Pharmacokinetic parameters of GC4419 from Clinical Study GT-001 ......................33 
Table 7: 
Comparison of WHO Scale vs. NCI-CTCAE v4 for Oral Mucositis .........................36 
Table 8: 
Time to Tumor Progression in RTOG 0129 and RTOG 0522 (Fakhry et.al. -
ref 46) ..........................................................................................................................42 
Table 9: 
Chemoradiation and GC4419 Example Administration Schedule: 35 Doses 
of GC4419 (7 Week Schedule) ...................................................................................53 
Table 10: Pharmacokinetic Sampling Schedule to Assess GC4419, Metabolites 
GC4570 and GC4520 .................................................................................................61 
Table 11: Adverse Event Severity ..............................................................................................74 
 
 
List of Figures 
Figure 1: 
OM scores by visit for individual patients; cohorts receiving 14 doses (3 
weeks) GC4419, GT-001 trial ....................................................................................29 
Figure 2: 
OM scores by visit for individual patients; cohorts receiving 112 mg/d of 
GC4419 for 20-30 doses (4-6 weeks), GT-001 trial ...................................................30 
Figure 3: 
OM scores by visit for individual patients; cohorts receiving 30 or 90 mg/d 
of GC4419 for 6-7 weeks, GT-001 trial .....................................................................31 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Definition 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
BSA 
Body Surface Area 
CAT 
Computerized Axial Tomography 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Tumor Volume 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ET 
Early Termination 
FACT-HN 
Functional Assessment of Cancer Therapy – Head and Neck 
FDA 
Federal Drug Administration 
FHNSI 
FACT Head and Neck Symptom Index 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
Gy 
Gray 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 


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Abbreviation or Specialist Term 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act 
HNC 
Head and Neck Cancer 
HPV 
Human Papilloma Virus 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMRT 
Intensity-Modulated Radiation Therapy 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISOO 
International Society of Oral Oncology 
IV 
Intravenous 
IVRS 
Interactive Voice Randomization System 
MASCC 
Multinational Association of Supportive Care in Cancer 
MTS 
Mouth and Throat Soreness 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NCS 
Non-Clinically Significant 
OAE 
Other Significant Adverse Event 
OC 
Oral Cavity 
OM 
Oral Mucositis 
OMDQ 
Oral Mucositis Daily Questionnaire 
OMWQ 
Oral Mucositis Weekly Questionnaire 
OP 
Oropharynx 
PBO 
Placebo 
PD 
Pharmacodynamic 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PRO 
Patient Reported Outcome 
PTV 
Planning Tumor Volume 
QOL 
Quality of Life 


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Abbreviation or Specialist Term 
Definition 
REB 
Research Ethics Board 
RNA 
Ribonucleic Acid 
ROS 
Reactive Oxygen Species 
RT 
Radiation Therapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SCC 
Squamous Cell Carcinoma 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SOD 
Superoxide Dismutase 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 


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4. 
INTRODUCTION 
4.1. 
Background 
4.1.1. 
Oral Mucositis in Patients Treated with Chemoradiation for HNC 
Oral mucositis (OM) is a common, problematic, and painful complication of cancer therapy, 
particularly in regimens that include radiation to the head and neck.1   Oral mucositis is readily 
graded using the commonly-used five-point World Health Organization (WHO) scale, in which: 
• Grade 0 = No mucositis 
• Grade 1 = Pain and erythema 
• Grade 2 = Ulceration but no compromise in diet (able to eat solid food) 
• Grade 3 = Ulceration with ability to eat only liquids 
• Grade 4 = Ulceration with inability to eat/requirement for tube or parenteral feeding   
A majority of patients receiving combined chemoradiotherapy for head and neck cancer (HNC) 
can be expected to develop severe (WHO Grade 3-4) OM,2 and nearly all HNC patients 
receiving RT with concurrent cisplatin are expected to develop ulcerative OM (WHO Grade 2 or 
higher).3  
Standard chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck 
(SCCHN), whether in the post-operative or definitive setting, currently consists of intensity-
modulated radiation therapy (IMRT) plus systemic therapy.  Common systemic treatment is with 
single-agent cisplatin, administered either q3 weeks or once weekly schedule.4, 5, 6, 7  The 
monoclonal antibody cetuximab has also been shown to increase the efficacy of radiotherapy for 
locally advanced head and neck cancer,8  and the combination of IMRT plus either single-agent 
cisplatin or single-agent cetuximab is currently being tested head-to-head for patients with 
human papilloma virus (HPV)-related oropharyngeal cancer in the ongoing RTOG 1016 trial. 
Unpublished observations for a group of approximately 300 patients treated with intensity-
modulated radiation therapy (IMRT) plus single-agent cisplatin for cancers of the oral cavity or 
oropharynx, without additional treatment to prevent OM, suggest that approximately 70% of 
patients may be expected to develop severe OM, at a median cumulative IMRT dose delivered of 
approximately 40 Gy (S. Sonis, Dana-Farber Cancer Institute), as summarized in Table 2.  In 
addition, two published Phase 3 studies of palifermin in patients receiving RT plus single-agent 
cisplatin for SCCHN reported an overall incidence of severe (WHO Grade 3-4) OM among 
placebo patients of 67% in one study and 69% in the other.9,10  
 
 
 


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Table 2: 
Cumulative Onset of WHO Grade 3-4 OM vs. Total IMRT in Patients 
Receiving Concurrent Single-Agent Cisplatin 
At Total Delivered IMRT 
Estimated Cumulative Incidence of Severe OM (WHO Grade 3-4)  
+/-5%, N= ~300 Patients, Multiple Studies 
At any time during/post IMRT 
73% 
@ total 20-29 Gy 
20% 
@ total 30-39 Gy 
40% 
@ total 40-49 Gy 
50% 
@ total 50-59 Gy 
60% 
@ total 60-70 Gy 
70% 
Median Onset of Severe OM 
40 Gy 
Adding cetuximab to standard chemoradiation regimens for HNC increases the risk of significant 
OM,7 while cetuximab without additional chemotherapy has been reported in one study to 
increase the risk of OM in patients receiving radiation modestly, if at all.8  
Among patients being treated for HNC, OM follows a predictable and well-documented course.11 
By the end of the first week of treatment (typically cumulative radiation doses of 10 Gy), 
erythema of the oral mucosa is usually seen and patients complain of discomfort that is 
characterized as burning.  This relatively mild pain escalates between the second and third week 
of treatment (radiation doses of 20 Gy to 30 Gy), when frank ulceration of the mucosa develops.  
Lesions at this stage often necessitate a modification in food intake and a marked increase in the 
need for analgesics.  Individual ulcers frequently coalesce as radiation progresses resulting in 
confluent injury affecting many aspects of the oral mucosa.  Pain intensifies and may be 
inadequately controlled even with aggressive narcotic therapy.12 
Oral mucositis is a treatment-induced morbidity that has substantial impact on day-to-day 
functioning.  In addition to the common need for, and inadequate pain control with, narcotics, the 
profound clinical impact of OM also includes weight loss, difficulty eating and swallowing, 
dehydration, need for nutritional support, and reduced performance status,12 as well as secondary 
infections at sites of ulcerative OM,13 and diminished quality of life (QOL) outcomes.14  Patients 
with HNC may also suffer the additional complications of short- and long-term xerostomia, taste 
change, and trismus related to post-radiation fibrosis.   
Besides its symptomatic toll, OM is associated with a number of serious medical complications 
and negative health economic outcomes. Among patients treated for HNC, even mild mucositis 
results in more frequent hospitalization and breaks in treatment, introducing the risk of 
compromised anti-tumor efficacy.15, 16  In granulocytopenic patients, mucositis is strongly 
associated with an increased risk of bacteremia and sepsis.17  Adverse health economic outcomes 
include increased analgesic and antibiotic use, increased number of febrile days, need for 
parenteral nutrition, prolonged length of hospital stay, and increased resource use and associated 
cost.18  


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4.1.2. 
Oral Mucositis is an Unmet Medical Need 
Oral mucositis prevention and management remains a substantial unmet need. For years, there 
has been no substantial change in its management.19  Current guidelines20 from the Multinational 
Association of Supportive Care in Cancer and the International Society of Oral Oncology 
(MASCC/ISOO) limit recommended or suggested interventions to prevent OM to: 
• Palifermin in the setting of high-dose chemotherapy and total body irradiation, 
followed by autologous hematopoietic stem cell transplantation (HSCT), for a 
hematological malignancy; 
• Oral cryotherapy in the setting of 5-fluorouracil therapy or chemotherapy/HSCT; 
• Low-level laser therapy in the setting of chemotherapy/HSCT or chemoradiotherapy 
for HNC; 
• Benzydamine mouthwash in the setting of HNC treated with moderate-dose RT, 
without concomitant chemotherapy; 
• Oral zinc supplements in the setting of radiation or chemoradiation; 
• Oral care protocols across all cancer treatment modalities. 
Narcotics and doxepin mouthwash are recommended or suggested by MASCC/ISOO for the 
treatment of OM-related pain.  A number of other agents currently used to treat OM, while 
designed to palliate associated pain or manage infection, do not alter the underlying biologic 
processes that give rise to OM.  MASCC/ISOO currently recommends or suggests against the 
use of some agents that have historically been used (e.g., antimicrobial mouthwashes, sucralfate, 
chlorhexidine mouthwash), citing evidence for lack of effectiveness against OM in one or more 
treatment settings. 
At present, palifermin is the only FDA-approved drug intervention for OM but its use (patients 
receiving HSCT for hematologic malignancies) is limited to a very small cohort (4%) of the at-
risk population; viz., OM associated with conditioning regimens prior to stem cell transplant for 
the treatment of hematologic malignancies.21   
A number of medical devices are in the market, but generally lack sufficient data to allow 
recommendation.  The mucoadhesive MuGard™ is indicated as a palliative treatment for the 
management of OM22  but requires administration four to six times per day for optimal effect and 
does not alter the mechanism of OM.  The oral gel Gelclair® has a similar use and effect for OM 
or oral irritation due to other causes but does not affect the mechanism of OM.  Caphosol® 
(supersaturated calcium phosphate rinse) is indicated for xerostomia or as an adjunct to standard 
oral care for OM23 but failed to reduce the incidence of ulcerative or severe OM in a recently-
published Phase 2 study.24   The lipid-based oral barrier rinse Episil® and the bacteriostatic rinse 
GelX® (zinc gluconate-taurine complex) may be used for pain related to OM but do not affect the 
mechanism causing OM. 
4.2. 
GC4419 
GC4419 is a novel, highly stable manganese-containing macrocyclic ligand complex with a 
molecular weight of 483, whose activity mimics that of naturally occurring superoxide dismutase 


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(SOD) enzymes.  It is therefore a prototype of a new class of drugs termed selective SOD 
mimetics.   
GC4419 selectively removes superoxide anions without reacting with other reactive oxygen 
species, including nitric oxide, hydrogen peroxide, and peroxynitrite.  In addition, unlike native 
SOD, GC4419 is not deactivated by nitration.  Nonclinical data have identified GC4419 as a 
promising new radioprotective, anti-cancer and anti-inflammatory agent.  Thus, GC4419 was 
active as a radio-protectant in animal models of cancer radiation therapy and added to the 
activity of chemotherapeutic agents in animal models of cancer. Importantly, GC4419 did not 
interfere with the anti-tumor effects of either radiation therapy or chemotherapy in animal 
models of cancer. 
GC4419 is being developed for the initial indication of “Reduction of the Severity and Incidence 
of Radiation and Chemotherapy Induced Oral Mucositis” under IND 111,539 with the Division 
of Oncology Products I, United States Food and Drug Administration. 
4.2.1. 
Biological Rationale for GC4419 in Radiation/Chemotherapy Induced OM 
Under normal circumstances superoxide (O2-) is a by-product of mitochondrial cellular 
respiration and is also produced by activated phagocytes.   Since superoxide is extremely 
reactive with biological molecules, it is quite toxic to cells.  In all studied species, this potentially 
toxic superoxide burden is normally contained by a complement of Superoxide Dismutase (SOD) 
enzymes.25  In vertebrates, SOD enzymes are present in the cytoplasm (SOD1 Cu/Zn based), 
mitochondria (SOD2, Mn based) and extracellular spaces (SOD3, Cu/Zn based).  Superoxide 
dismutases are a class of oxidoreductase enzymes that dismutate superoxide into molecular 
oxygen and hydrogen peroxide.  
The control of the free radical flux derived from oxygen is jeopardized in many circumstances in 
which superoxide production is excessive or if the breakdown of superoxide is compromised. 
This over-production of superoxide can overwhelm the body’s ability to eliminate it via catalytic 
dismutation and lead to a variety of superoxide initiated or mediated disease states, including 
OM. 
Ionizing radiation damages cells by transferring sufficient energy to intracellular atoms or 
biomolecules to modify their normal properties and functions. Since approximately 70% of an 
average cell consists of water, radiolytic hydrolysis is by far the primary triggering event 
following the exposure of cells and tissues to ionizing irradiation, e.g., as in radiation therapy 
(RT) for the treatment of cancer.26    
Radiolytic hydrolysis leads to the formation of a number of reactive oxygen species (ROS), 
including predominantly the superoxide anion (O2-). Therapeutic radiation damages cancer cells 
by abruptly but transiently increasing tissue ROS, including superoxide. Normal cells in the 
radiation field counter these damaging effects by detoxifying ROS via their intact redox 
protective enzyme systems (SOD, catalase, glutathione peroxidase), converting hydrogen 
peroxide into water and molecular oxygen, and by the activation of DNA repair mechanisms. In 
cancer cells, it has been suggested that exogenous SOD and SOD mimetics, by reducing 
intracellular superoxide (a proliferation trigger) and increasing hydrogen peroxide (an apoptosis 
trigger) shifts the critical cellular redox balance reducing the proliferative drive and increasing 
the apoptotic drive.27  


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Recent research has demonstrated that the pathogenesis of mucositis involves more than just 
direct clonogenic cell death induced non-specifically on rapidly dividing basal epithelial cells.  
Rather, basal epithelial cell death is mediated by a wide range of mechanistic pathways; at least 
14 canonical pathways have been identified as being involved in HNC treatment toxicities.28  
The generation of reactive oxygen species (ROS) by chemoradiation, for example, leads to a 
number of signaling pathways in the submucosa that then target the epithelium and result in loss 
of epithelial renewal and the development of ulceration.29  ROS, and in particular O2•-, are 
believed to play a central role in the initiation of tissue injury and up-regulation of inflammatory 
cytokines, with subsequent signal amplification and mucosal inflammation and ulceration.30  
Furthermore, differences in polymorphisms that encode for glutathione S-transferase, an enzyme 
that provides protection from ROS, have been associated with increased risk for radiation- and 
chemotherapy-induced injury to both the oral mucosa and skin.31  
Taken as a whole, this suggests that an agent that efficiently and rapidly removes O2•- offers a 
treatment paradigm for preventing or controlling OM.  Numerous published studies indicate that 
OM, esophagitis, pneumonitis, fibrosis, or other normal-tissue radiation damage may be reduced 
by treatment with liposomally encapsulated exogenous MnSOD or a MnSOD transgene, 
exogenous Cu/Zn SOD, or a dismutase mimetic enantiomerically related to GC4419.32, 33, 34, 35, 36 
4.3. 
Pre-Clinical GC4419 Data 
4.3.1. 
Pre-Clinical Data with GC4419 in Hamster Models for Radiation-Induced OM 
Pre-clinically, GC4419 has been shown to reduce the duration of severe OM in the hamster 
cheek pouch model.  When administered 30 min before and 12 hours after irradiation (40 Gy) of 
the everted buccal cheek pouch of Syrian golden hamsters, GC4419, like its enantiomer GC4403, 
accelerated the resolution of OM and reduced the percentage of animal days with severe OM (a 
mucositis score ≥3), in a dose-dependent fashion, compared with a vehicle control group.37   
Effective plasma concentrations of GC4419 in this well-established animal model of OM were 
similar to those previously found achievable in normal human volunteers.38  
In a separate study in the same model assessing fractionated radiation, hamsters received a total 
of 60 Gy in eight fractions of 7.5 Gy each over 10 days, on Days 0-3 and 6-9.  GC4419, 10 or 30 
mg/kg i.p, was administered 30 minutes before irradiation by two schedules: on Days 0-3 and 6-
9; or on Days 0, 2, 6, and 8 (10 animals per group).  GC4419 significantly reduced severe OM, 
but only when administered at a dose of 30 mg/kg before each irradiation.39  
4.3.2. 
GC4419 is not Tumor Protective in Non-Clinical Cancer Models. 
Importantly, GC4419 does not interfere with the antitumor efficacy of radiation therapy or 
cancer chemotherapeutic agents in any in vitro or in vivo models evaluated to date.  This 
supports the findings for this differential effect on cancer and normal cells is due to differences 
in H2O2 sensitivity between these cells, as noted above.  SOD enzymes in normal cells rapidly 
convert O2•- to H2O2 which is then rapidly detoxified to water by catalase, glutathione 
peroxidase and related enzymes.  Cancer cells may be deficient in these enzymes, but also tend 
to be especially sensitive to elevated H2O2.  The addition of an SOD mimetic (such as GC4419) 
more rapidly drives O2•- to H2O2, creating a burden that is markedly more toxic to tumor cells 
than normal cells.  In vitro, GC4419 protects a variety of normal cell types from the effects of 


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radiation while sensitizing lung and head-and-neck cancer cell lines, consistent with the literature 
on SOD enzyme effects.  GC4419 did not antagonize the growth-inhibitory effects of cisplatin 
on the cisplatin-sensitive CT26 tumor cell line.  In fact, at concentrations >1 µM cisplatin, 
GC4419 enhanced the cisplatin effect.  As expected, GC4419, when added alone, inhibited the 
O2•- dependent proliferation of CT26 cells.  In addition, Galera has evaluated GC4419 as a 
single agent against multiple tumor cell lines in vitro and, in every case, tumor cell growth and 
proliferation was either inhibited or not affected (data on file, Galera Therapeutics, Inc.).    
In vivo, GC4419 does not diminish, but may enhance, the anti-tumor effects of radiation or 
chemotherapy.  Notable are results in the human lung tumor xenograft, H1299, and the human 
HNC tumor xenograft, FaDu/HTB-43.  In the H1299 model, GC4419 appeared modestly to 
increase the antitumor effect of cisplatin plus radiation given in fractions of approximately 2 Gy.  
In the FaDu model, GC4419 neither enhanced nor antagonized the anti-tumor effect of radiation.  
In the FaDu model, in parallel cohorts of tumor-bearing animals, plasma concentrations of 
GC4419 assayed 0, 5, 15, 30, and 60 minutes following irradiation demonstrated plasma 
exposures of GC4419 that exceeded the levels shown to be efficacious in the previously 
described OM model in hamsters (data on file, Galera Therapeutics, Inc.). 
Further, results from ongoing Galera-sponsored studies (M. Story, University of 
Texas/Southwestern, personal communication) suggest that GC4419 may more greatly 
radiosensitize tumors when radiation is given by a hypofractionated schedule.  In another 
experiment in the H1299 model, a single dose of 20 mg/kg GC4419 caused a tumor growth delay 
of 22 days vs. vehicle control, comparable to results with single agent cisplatin (21 day tumor 
growth delay).  A single radiation fraction (day 0) of 18 Gy produced a 32-day tumor growth 
delay compared to vehicle.  The combination of GC4419 and 18 Gy of radiation produced a 
tumor growth delay of 90 days compared to vehicle and 57 days compared to radiation alone.  
These results were similar to those obtained by the combination of cisplatin and radiation and 
were not statistically different from results when GC4419 was added to the combination of 
radiation and cisplatin.    
Galera has conducted tumor growth delay studies in several other in vivo tumor models, 
including colon, HNC, lung and melanoma.  In every case, tumor growth was either slowed or 
not affected, and in no case has GC4419 interfered with the anti-tumor effects of chemotherapy 
(cisplatin, gemcitabine, cyclophosphamide, paclitaxel, irinotecan, and doxorubicin) or 
radiotherapy (data on file, Galera Therapeutics, Inc.). 
Results of experiments with GC4419 in cancer tumor models are further described in the 
GC4419 Investigator’s Brochure.  Additional non-clinical studies are planned to further elucidate 
mechanisms of any anti-tumor interaction between radiation and GC4419. 
4.4. 
Phase I Study of GC4419, GT-001  
4.4.1. 
Clinical Data with GC4419 in Radiation/Chemotherapy Induced OM 
GC4419 has been studied in a Phase 1b/2a trial, GT-001 (NCT01921426), in combination with 
IMRT and single agent cisplatin, in the treatment of patients with squamous cell carcinoma of 
the oral cavity (OC) or oropharynx (OP) for whom the planned IMRT/cisplatin regimen is 
medically indicated.  In the IMRT regimen, patients received approximately 2 Gy of IMRT once 
daily, Monday-Friday, up to a total of approximately 70 Gy administered over 7 weeks.   


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Cisplatin was administered either every 3 weeks for 3 doses (80-100 mg/m2), or weekly for 6-7 
doses (30-40 mg/m2).  GC4419 was administered by 60-minute IV infusion each day (M-F) prior 
to that day’s IMRT fraction, with IMRT administered within 60 minutes of the end of GC4419 
infusion. 
The primary objective of the GT-001 clinical study was to characterize the safety profile of 
GC4419 when administered with the IMRT/platinum regimen, with key secondary objectives of 
reduction in the incidence, severity, and/or duration of OM experienced by patients.  The trial 
followed a serial cohort (3+3) dose escalation design.  
Under an early version of protocol GT-001 patients received GC4419 prior to each of the first 14 
or 20 doses of IMRT.  Serial cohorts of patients were assigned to daily doses of 15, 30, 50, 75, or 
112 mg (absolute dose).   After FDA review of a Type A meeting request (IND serial 0016, 
submitted April 2, 2014 with FDA Meeting Preliminary Comments April 28, 2014) the protocol 
was amended to provide for serial patient cohorts to receive GC4419 prior to the first 25, 30, or 
all 35 dose fractions of IMRT, at daily doses previously shown not to exceed the maximum 
tolerated dose (MTD).   Under this amendment, serial cohorts of patients were assigned to 
receive 112 mg/d for 25 or 30 doses, 90 mg/day for 30 or 35 doses, and 30 mg/d for 35 doses.  
Studying longer durations of dosing was based on the hypothesis that administration of GC4419 
throughout the duration of IMRT would be needed for optimal efficacy against OM. 
A total of 46 patients were enrolled.  Of these, 45 were evaluable for safety and 43 were 
evaluable for OM (Table 3): 
Table 3: 
GT-001 Enrollment 
Dose Cohort 
# enrolled 
# evaluable for safety 
# evaluable for OM 
15 mg/d x 14 doses 
4 
4 
4 
30 mg/d x 14 doses 
3 
3 
3 
50 mg/d x 14 doses 
4 
4 
4 
75 mg/d x 14 doses 
3 
3 
3 
112 mg/d x 14 doses 
8 
7 
6 
112 mg/d x 20 doses 
3 
3 
3 
112 mg/d x 25 doses 
3 
3 
3 
112 mg/d x 30 doses 
5 
5 
4** 
90 mg/d x 30 doses 
3 
3 
3 
90 mg/d x 35 doses 
6 
6 
6 
30 mg/d x 35 doses 
4 
4 
4 
**one patient enrolled at 112 mg/d x 30 doses actually received 87 mg/d, per protocol provision, and is 
included with others at 90 mg/d x 30 doses in presentations of OM efficacy 
4.4.2. 
Oral Mucositis Clinical Data from GT-001 
As of July 8, 2015, treatment was complete for all patients and unaudited OM data were 
available for the 43 patients evaluable for OM. The OM evaluations indicate that, compared with 
historical expectations: 
• The overall incidence of severe (WHO Grade 3 or 4) OM appears reduced; 


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• Severity of OM (specifically, Grade 4 OM) appears to be lowered when GC4419 
treatment is extended for 6-7 weeks; 
• Onset of severe OM appears delayed; 
• Duration of severe OM appears reduced, particularly with the longer treatment schedules. 
In general, efficacy to reduce the incidence and severity of OM appeared greatest with more 
prolonged GC4419 dosing schedules.  However, there was not a clear relationship between 
absolute daily dose and OM results; excellent efficacy was apparent even for patients who 
received 30 mg/d.  
The overall incidence of Grade 3-4 OM (all cohorts, pooled) is summarized, in comparison with 
the matched historical data, in Table 4, below:    
Table 4: 
Cumulative Onset of WHO Grade 3-4 OM vs. Total IMRT in GT-001, 
Compared with Unpublished Experience from S. Sonis 
At Total Delivered 
IMRT 
Week of 
Therapy 
Expected Cumulative Incidence of 
Severe (WHO Grade 3-4) OM (+/-5%) 
GC4419 Results  
All Cohorts, N=43 
At any time 
during/post IMRT 
--- 
73% 
51% (22/43)1 
@ total 20-29 Gy 
3 
20% 
5% (2/43) 
@ total 30-39 Gy 
4 
40% 
12% (5/43) 
@ total 40-49 Gy 
5 
50% 
26% (11/43) 
@ total 50-59 Gy 
6 
60% 
37% (16/43) 
@ total 60-70 Gy 
7 
70% 
47% (20/43) 
1Two patients had first severe OM at a post-IMRT visit; Gy to onset of severe OM set at 70 for these 2 patients 
Sources:  Sonis, personal communication; Monitored, unaudited Galera GT-001 clinical data 
It is noteworthy that only 2 of 43 patients had experienced Grade 3 OM (no Grade 4) by the end 
of the third week of IMRT, and only 5 of 43 had experienced Grade 3 OM (no Grade 4) by the 
end of the fourth week of IMRT.  This compares favorably with the published experience of Le 
et.al.9 and Henke et.al.10 in which approximately 20% of patients receiving placebo and 
approximately 15% of patients receiving palifermin had developed Grade 3 or 4 OM by the end 
of 3 weeks, and approximately 40% of patients receiving placebo and approximately 30% of 
patients receiving palifermin had developed Grade 3 or 4 OM by the end of 4 weeks.9,10 
However, a single metric such as overall incidence does not fully characterize the OM efficacy 
data for GC4419.  Figure 1, Figure 2 and Figure 3 demonstrate each individual patient’s OM 
experience over time (one row per patient).  In the aggregate, these results appear to confirm 
that, as treatment duration is increased, the incidence of severe OM is lower than expected, while 
severe OM, when it occurs, is delayed in onset, lower in severity (with Grade 4 OM rare in 
patients receiving 6-7 weeks of GC4419), and shorter in duration.   
Table 5 tabulates OM results by several measures, vs the historical matched data and the 
published placebo data of Le and Henke.  These measures include incidence of severe OM 
through the “landmark” point of 60 Gy delivered to tumor (approximately 6 weeks), a fixed 
reference point in the treatment course.  


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Figure 1: 
OM scores by visit for individual patients; cohorts receiving 14 doses (3 weeks) GC4419, GT-001 trial 
 
Historical incidence Gr 3+4:                    20%              40%             50%            60%              70%    
8
9
10
11
12
13
14
15
Radiation Therapy 2Gy/day Mon-Fri x 7 weeks
MV = missed Visit (last grade toxicity carried forward)
Grade 3 OM
Grade 4 OM
0
0
2
2
1
2
2
2
2
2
4
4
4
4
4
4
4
4
3
3
2
2
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
MV
MV
1
0
0
0
0
1
1
0
0
1
1
MV
MV
1
MV
0
0
2
0
0
1
0
0
0
0
0
0
2
0
0
1
0
0
2
MV
2
2
2
2
2
0
0
0
0
2
2
2
0
0
0
MV
0
0
1
1
0
0
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
0
0
0
1
MV
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
1
1
1
3
3
3
3
1
0
0
0
0
0
1
1
2
3
3
3
3
4
4
4
4
0
1
0
2
0
2
2
2
2
2
2
2
3
2
2
MV
4
2
2
2
2
2
2
2
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
4
4
2
1
0
0
0
1
2
2
2
2
3
3
3
3
3
3
3
3
2
2
2
2
2
2
2
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
0
0
0
MV
MV
MV
4
3
4
3
4
3
4
MV
4
MV
4
MV
4
0
0
0
0
0
0
0
0
0
2
2
2
2
2
2
2
0
0
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
0
0
0
0
2
2
2
2
2
3
2
2
2
2
2
3
2
2
2
0
0
0
0
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
2
0
0
0
0
0
0
0
0
0
0
1
1
1
2
2
2
2
1
All Completed
3 Pts. Unevaluable because they were treated for <14 days (1 Pt. 3 doses, 1 pt 2 doses, 1 pt 10 doses) - off for events unrelated to GC4419
Post-Treatment Visits Weekly
75mg 
x14 days
112mg 
x
14 days
15mg 
x14 days
30mg 
x14 days
50mg 
x14 days
Week 1
Week 2
GC4419
Dose x Days
Week 3
Week 4
Week 5
Week 6
Week 7


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Figure 2: 
OM scores by visit for individual patients; cohorts receiving 112 mg/d of GC4419 for 20-30 doses (4-6 weeks), 
GT-001 trial 
 
Historical incidence Gr 3+4:                      20%            40%             50%            60%              70%    
8
9
10
11
12
13
14
15
Radiation Therapy 2Gy/day Mon-Fri x 7 weeks
MV = missed Visit (last grade toxicity carried forward)
Grade 3 OM
Grade 4 OM
0
0
0
0
0
0
1
0
0
0
2
2
2
2
1
0
0
0
1
1
1
1
1
1
2
2
0
3
0
0
3
3
4
2
MV
0
0
0
0
2
2
2
2
2
2
2
2
2
3
3
3
3
2
2
2
0
0
0
1
3
3
3
MV
3
3
3
3
3
3
3
3
3
MV
3
2
2
1
0
0
0
0
0
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
2
2
2
2
2
2
2
2
2
2
2
4
2
1
0
0
2
2
2
2
2
2
2
3
4
4
4
4
4
4
3
2
2
2
0
0
0
0
0
0
2
2
MV
2
0
3
2
2
2
2
2
2
4
0
*All 3 patients had interruptions in treatment and none actually received 112mg for 30 days
Week 3
Week 4
Week 1
Week 2
112mg 
x 20 days
112mg
x 25 days
112mg*
x 30 doses
GC4419
Dose x Days
Week 5
Week 6
Week 7
Post-Treatment Visits Weekly


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Figure 3: OM scores by visit for individual patients; cohorts receiving 30 or 90 mg/d of GC4419 for 6-7 weeks, GT-001 trial 
 
8
9
10
11
12
13
14
15
Radiation Therapy 2Gy/day Mon-Fri x 7 weeks
MV = missed Visit (last grade toxicity carried forward)
Grade 3 OM
Grade 4 OM
0
0
0
0
1
0
1
2
2
2
2
2
2
2
1
0
0
0
0
1
2
2
2
0
2
2
2
2
2
2
2
2
2
2
0
0
0
1
0
2
2
2
2
3
2
2
2
3
MV
MV
MV
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
0
2
2
2
3
2
2
2
2
2
2
2
2
0
0
0
0
0
2
0
2
2
0
3
3
0
1
3
3
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
3
0
0
0
1
0
0
2
0
2
2
2
2
2
2
2
0
0
0
0
2
3
2
3
3
3
2
2
MV
MV
0
0
0
2
2
2
2
2
2
2
2
2
3
2
3
2
1
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
2
2
2
2
2
2
2
2
2
2
2
2
2
MV
0
0
0
0
0
0
0
2
0
0
2
2
2
2
2
Week
7
Post-Treatment Visits Weekly
90mg 
x
35 days
30mg 
x
35 days
90mg 
x 30 days
Week
3
Week
4
Week
5
Week
6
GC4419
Dose x 
Days
Week 
1
Week 
2
Historical incidence Gr 3+4:                        20%               40%                 50%               60%               70%      


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Table 5: 
OM parameters for GC4419 (GT-001 trial) compared with historical 
matched and published control data 
SEVERE ORAL MUCOSITIS (Grade 3&4) 
Comparison of Key Efficacy Parameters 
Comparative Historical Control Data 
GC4419 data 
Matched 
Data Set 
Placebo data from 
published Phase III trials 
Partial 
treatment 
(3 weeks) 
Full 
Treatment 
(6-7 weeks) 
S. Sonis 
Le et al  
(ref 9) 
Henke et al 
(ref 10) 
# Patients 
≈300 
94 
94 
20 
14 
INCIDENCE 
Grade 3+4 Incidence through 60 
Gray  
60% 
57% 
62% 
40% 
29% 
INTENSITY 
Grade 4 Overall Incidence 
20% 
19% 
26% 
25% 
0% 
ONSET 
Median Time to Onset of Grade 
3-4 (treatment days) 
28 
35 
32 
>54 
>50 
Median Radiation Dose to Onset 
(Gray) 
40 Gy 
Not stated 
Not stated 
70 Gy1 
70 Gy1 
DURATION 
Median Duration of Grade 3+4  
OM (Days) 
28 
26 
22 
4.5 
2.5 
1 All patients included. Assigns a value of 70 Gy to patients who never developed severe OM. 
Sources:  Sonis, personal communication; Galera monitored, unaudited data for GT-001 trial; references 9 and 10 
4.4.3. 
Clinical Safety Data with GC4419  
The most common adverse events observed in the GT-001 study were nausea, fatigue, dysgeusia, 
oropharyngeal pain, decreased white blood cell count, constipation, dry mouth, anemia, 
vomiting, diarrhea, decreased lymphocyte count, and decreased appetite. These and other 
adverse events observed are characteristic of the cisplatin/IMRT regimen in this patient 
population.  
The following mild to moderate adverse events were reported as possibly related to GC4419 for 
>10% of patients in the GT-001 study: nausea, vomiting, dry mouth, diarrhea, fatigue, dyspepsia, 
gastroesophageal reflux disease, dizziness, dysgeusia, weight loss, decreased appetite, headache, 
paresthesia, and hiccups. 
The following more severe adverse events were reported as possibly related to GC4419 in the 
GT-001 study: anemia, nausea, vomiting, gastroenteritis, low white blood cell count, low 
neutrophil count, weight loss, decreased appetite, arthritis, and reduced range of motion. As of 
21-Dec-2016 the following additional severe adverse events have been reported as possibly 
related to GC4419 in the GT-201 study: hypotension, diarrhea, unexplained fever, and 
bradycardia/syncope. 
Potentially mechanism-related facial tingling or paresthesia, possibly due to nitric oxide 
potentiation, was reported for several patients in the GT-001 study and appears related to 
GC4419 dose, occurring in 11/19 (58%) patients receiving 112 mg per dose, 5/9 (55%) patients 
receiving 90 mg/dose, but only 2/18 (11%) at lower doses.  This facial tingling/paresthesia was 
mild to moderate, and when it occurred it did so during GC4419 infusion with resolution shortly 
after the end of the infusion.  It was neither treatment-limiting nor troublesome to patients, and 
does not pose a meaningful safety risk. 


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Per their reported assessments, investigators considered two patients to have potentially dose-
limiting toxicities (DLTs), both at a daily dose of 112 mg: 
• One patient receiving 112 mg for 14 doses had an episode described as gastroenteritis 
(principally nausea and vomiting) requiring hospitalization.  This event occurred 
during the first three weeks of IMRT, and was reported as possibly related to GC4419 
because of the temporal association with days of GC4419 treatment, although the 
patient’s symptoms were not infusion-related.  Furthermore, the treating investigator 
reported that the event “probably” was attributable to cisplatin. 
• One patient enrolled to the 112 mg x 30 dose cohort experienced two episodes of 
nausea and vomiting requiring hospitalization, first after the fourth week of protocol 
therapy, then again after rechallenge with GC4419 and IMRT through the fifth week 
of treatment.  The treating investigators reported that the patient’s vomiting was 
possibly related to GC4419 but principally due to the presence of thick secretions 
complicating swallowing.  The patient also experienced Grade 3 hyponatremia that 
was initially reported as possibly related to GC4419, but that appears from the clinical 
events to be attributable to GI loss and poor intake of solutes.  While this patient’s 
events were reported as possibly related to GC4419, they may not constitute true 
dose-limiting toxicities of GC4419. Including these two cases, through August 6, 
2015 a total of 49 event terms have been reported as serious adverse events (SAEs) 
for 23 patients.  In some cases, a single medical event was reported as several event 
terms with identical or overlapping onset dates.  Only in the two cases described 
above were the events reported as possibly related to GC4419.  Other SAEs were 
judged not related to GC4419, but attributable to the combination of platinum and 
IMRT or to comorbidities and concomitant medications.   SAEs event terms reported 
for more than one patient include fever (5 patients), vomiting (5 patients), febrile 
neutropenia (4 patients), nausea (3 patients), and dehydration (2 patients).  
Pharmacokinetic (PK) sampling has been performed on Week 1 Day 2 and on Week 3 Day 3.  
Preliminary results shown in Table 6 below reflect available data for 32 patients from the GT-
001 study, with analysis of additional patients (e.g., treated at 90 mg/day) in progress. Results are 
consistent with modeled predictions (data not shown), and demonstrate increases in GC4419 
Cmax and AUC that are approximately dose-proportional.  There has been minimal accumulation 
of GC4419 in plasma with repeated dosing.  Exposure to active metabolites (which are 
substantially less active than the parent drug) is low compared with exposure to the parent drug 
GC4419 (data not shown).  
Table 6: 
Pharmacokinetic parameters of GC4419 from Clinical Study GT-001 
Dose Level 
(mg) 
C(max) (ng/mL) 
(Mean [SD]) 
AUC(0-inf) (ng.h/mL) 
(Mean [SD]) 
 
Week 1  
Week 3 
Week 1 
Week 3 
15 (n=4) 
474 [182] 
604 [308] 
883 [347] 
905 [466] 
30 (n=6) 
963 [152] 
991 [266] 
1650 [187] 
1810[408] 
50 (n=4) 
1450 [760] 
1620 [569] 
2780 [1570] 
3000 [1370] 
75 (n=3) 
2380 [940] 
3260 [406] 
4100 [2080] 
5000 [395] 


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Dose Level 
(mg) 
C(max) (ng/mL) 
(Mean [SD]) 
AUC(0-inf) (ng.h/mL) 
(Mean [SD]) 
112 (n=15) 
3410 [688] 
4130 [1290] 
6340 [1630] 
8090 [2660] 
4.5. 
Randomized Phase II Study of GC4419, GT-201 
In the present three-arm, randomized (1:1:1), placebo-controlled phase 2 trial, two doses of 
GC4419 (a “low” dose of 30 mg and a “high” dose of 90 mg) will be evaluated against placebo 
in patients with locally advanced, non-metastatic squamous cell HNC of the oral cavity or 
oropharynx.  All patients will receive a backbone regimen of cisplatin, either administered q3 
weeks, 80-100 mg/m2 or weekly 30-40 mg/m2 (investigator’s choice), plus IMRT administered 
in 2.0-2.2 Gy daily fractions, to a total dose of 60-72 Gy.   
The goals of the Phase 2 trial are to identify sufficient efficacy of GC4419, in the form of 
reduced duration, incidence, and severity of OM; to suggest clinical benefit and indicate that 
confirmation of such benefit is likely in a subsequent pivotal trial; and to inform the design of 
that trial.  Accordingly, the design of the Phase 2 trial, including the sample and target effect 
sizes, is intended to provide data sufficiently robust for GT-201 to guide the design of a future 
pivotal, registration-directed Phase 3 trial of GC4419 in the present indication.  
GT-201 is a placebo-controlled, double-blind trial.  Galera believes that the estimated incidences 
of severe OM as communicated by Sonis (Table 2) are likely to be accurate, because the data 
supporting them are pooled from a set of patients matched for tumor site, IMRT, and single-
agent cisplatin treatment, and because they appear to agree closely with published data, including 
the placebo experience in the two similarly-designed trials conducted with palifermin.  However, 
because of the risk of bias, the possibility of reductions of severe OM arising solely from 
ongoing refinements in the delivery of radiation therapy, and the early stage of GC4419’s 
development justifying equipoise, the placebo-controlled design has been chosen.  Similarly, this 
trial is double-blinded to reduce the risk of bias in the primary and secondary endpoints. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective of this study will be to evaluate and compare the duration of severe OM, 
as assessed from the first determination of ≥ Grade 3 OM to the first instance of non-severe OM 
(≤ Grade 2), without a subsequent instance of ≥ Grade 3.     
5.1.1. 
Rationale for Primary Endpoint 
The WHO scale is commonly used to assess OM in clinical care and research settings.   It was 
developed as a standard toxicity reporting index. It has evolved into the most accepted outcome 
for efficacy testing of drugs as it has been shown to meet key characteristics for clinical studies: 
• Accurate reflection of the severity and course of the objective and subjective changes 
of mucositis. 
• Easy to teach with a minimal inter-observer variability. 
• Does not require measurement of lesions. 
• Sensitive enough to discriminate treatment efficacy. 
• Clinically meaningful and easily interpreted endpoints for clinicians, patients and 
regulatory agencies. 
• The WHO scale has been used as the primary efficacy endpoint for many studies and 
is accepted internationally.   
There is precedent for severe OM on the WHO scale being used as the basis for drug approval.  
Palifermin (Kepivance®) is indicated to decrease the incidence and duration of severe oral 
mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring 
hematopoietic stem cell support, when the preparative regimen is predicted to result in WHO 
Grade > 3 mucositis in the majority of patients.  Approval of palifermin was based on a reduction 
in the number of days during which patients experienced severe oral mucositis (Grade 3/4 on the 
WHO (World Health Organization) scale); other analyses included the incidence, duration, and 
severity of oral mucositis and the use of opioid analgesia.43   Additional studies of agents to 
reduce OM—notably the two published studies of palifermin in the HNC population9, 10 also 
have used the WHO scale.   
The duration of severe OM is planned as the single primary endpoint of this Phase 2 trial.  
Secondary and exploratory endpoints (see sections 5.2  and 5.3, below) are expected to provide 
important and clinically relevant data supporting the primary endpoint, as well as data to guide 
the selection of a primary endpoint for a future pivotal trial. 
Because of the nature of the WHO grading scale (See Section 20), improvement of meaningful 
magnitude in the primary endpoint implies clinical benefit.  While ulcerative (Grade 2) OM is 
very common, its functional consequences may be open to question.  However, by definition, 
WHO Grade 3 OM entails a change in diet, and WHO Grade 4 OM includes inability to eat, 
requiring parenteral or tube feedings.   


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It may be noted here that many reports of OM in clinical trials use the NCI-CTCAE, in which the 
grading of OM is different from the WHO scale (Table 7).  Whereas the WHO criteria have been 
stable for years, NCI criteria have changed markedly with every new version.  The NCI criteria 
have found their greatest application in describing mucositis as an AE associated with anti-
cancer regimens, not as an instrument to assess intervention efficacy. 
Table 7: 
Comparison of WHO Scale vs. NCI-CTCAE v4 for Oral Mucositis  
OM Grade 
WHO Scale 
NCI-CTCAE v4 
0 
No mucositis 
No mucositis 
1 
Pain and erythema 
Asymptomatic or mild symptoms; 
intervention not indicated 
2 
Ulceration but no compromise in diet 
(able to eat solid food) 
Moderate pain; not interfering with oral 
intake; modified diet indicated 
3 
Ulceration with ability to eat only liquids 
Severe pain; interfering with oral 
Intake 
4 
Ulceration with inability to 
eat/requirement for tube or parenteral 
feeding 
Life-threatening consequences; 
urgent intervention indicated 
As noted, the WHO scale will be used in GT-201.  Separate grading of OM according to the 
CTCAE will not be performed. 
5.2. 
Secondary Objectives 
• To evaluate and compare the safety of GC4419 at the treatment assignment of each 
respective arm 
• To evaluate and compare the effects of GC4419, administered at each of two daily 
doses vs. placebo, on the cumulative incidence of severe OM, defined as any 
occurrence of WHO Grade 3-4 OM, from the first IMRT fraction through the delivery 
of the 30th IMRT fraction (approximately 60 Gy delivered to tumor)      
• To evaluate and compare the cumulative incidence of severe OM from the first IMRT 
fraction through the last IMRT fraction   
• To evaluate and compare the cumulative incidence of Grade 4 OM from the first 
IMRT fraction through the last IMRT fraction  
• To evaluate and compare onset of severe OM expressed as the number of IMRT 
fractions delivered at onset of severe OM 
• To evaluate and compare the effect of treatment assignment on tumor outcomes 
(locoregional failure, distant metastases, progression-free survival, overall survival) 
5.3. 
Exploratory Objectives 
• To evaluate and compare duration of severe OM among subjects with severe OM 


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• To evaluate and compare the time to onset of severe OM: expressed both as 
cumulative IMRT dosage and as time (days) at onset of severe OM 
• To evaluate and compare the time to onset of severe OM among subjects with severe 
OM: time (days), cumulative IMRT dosage, and number of IMRT fractions delivered 
at onset of severe OM 
• To evaluate and compare the duration of severe OM, assessed by the number of 
instances of severe OM of ≥ 7 days’ duration, defined as severe OM recorded at two 
or more consecutive OM evaluations 
• To evaluate and compare severe OM incidence from the first IMRT fraction through 
the end of post-IMRT early follow-up; post-IMRT early follow-up will extend for up 
to eight weeks post the last IMRT fraction administered or until a given patient’s OM 
is WHO Grade 0 or 1   
• To evaluate and compare cumulative severe OM incidence at cumulative delivery of 
20-29, 30-39, 40-49, or 50-59 Gy of IMRT 
• To evaluate and compare the duration of Grade 4 OM from the first IMRT fraction 
through the last IMRT fraction 
• To evaluate and compare the areas under the OM-severity vs. cumulative IMRT 
dosage curves 
• To evaluate and compare the number and percentage of patients with severe OM on 
more than one visit prior to Week 6, Visit 2 
• 
To evaluate and compare the total number of assessments (per patient) of severe OM through 
the end of IMRT 
• To evaluate and compare the effects of GC4419 on the incidence, onset, and duration 
of ulcerative (≥ Grade 2) OM 
• To evaluate and compare treatment delivery and delays (number and duration of 
delays) of IMRT and cisplatin 
• To evaluate and compare the effects of GC4419 on other specific toxicities of interest 
associated with concurrent chemoradiation:  xerostomia, trismus, fatigue, weight loss, 
radiation dermatitis, and dysgeusia (changes in taste) 
• To evaluate and compare the effects of treatment on patient-reported outcomes as 
obtained using the Oral Mucositis Daily Questionnaire (OMDQ) 
• To evaluate and compare the use of narcotic analgesics by patients according to 
treatment assignment 
• To evaluate and compare frequency, use, and reasons for use of gastrostomy tubes  
• To evaluate and compare the use and complications of indwelling venous access 
devices 
• To evaluate and compare the frequency and reasons for unscheduled hospitalizations 


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• To assess the effects of treatment assignment on circulating cytokine levels and gene 
expression levels 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
GT-201 is a randomized, double-blind, placebo-controlled, multi-center study conducted in the 
US and Canada to evaluate GC4419 administered IV to reduce the duration, incidence, and 
severity of radiation induced oral mucositis in patients receiving chemoradiation for SCCHN, 
limited to the oral cavity or oropharynx.   
6.2. 
Treatment Plan and Duration of Therapy 
Patients will be randomized equally to one of three treatment arms:  
Arm A: 
30 mg GC4419 per day (60 min IV infusion, to complete within 60 minutes prior 
to IMRT), concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-
72 Gy over approximately seven weeks, plus cisplatin administered 80-100 
mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 
doses (investigator’s choice) 
Arm B: 
90 mg GC4419 per day (60 min IV infusion, to complete within 60 minutes prior 
to IMRT), concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-
72 Gy over approximately seven weeks, plus cisplatin administered 80-100 
mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 
doses (investigator’s choice) 
Arm C: 
Placebo daily (60 min IV infusion, to complete within 60 minutes prior to IMRT), 
concurrent with daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over 
approximately seven weeks, plus cisplatin administered 80-100 mg/m2 once every 
three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses (investigator’s 
choice) 
Planned radiation treatment fields must include at least two oral sites (buccal mucosa, floor of 
mouth, tongue, soft palate) that are each planned to receive a total of ≥ 50 Gy. Note, unavoidable 
doses of at least 50 Gy, to include entrance, exit, and scatter doses, still constitutes planned 
radiation. 
GC4419/placebo will be given intravenously in a one hour infusion. IMRT must be initiated as 
soon as possible upon completion of the GC4419/placebo infusion but no later than 60 minutes 
following the end of the GC4419/placebo infusion.  
GC4419/placebo will be given beginning on the first day of radiation and continuing daily, 
concurrent with each dose of IMRT, to a cumulative radiation dose of approximately 60-72 Gy. 
If IMRT is not administered on any given day due to a treatment break or unforeseen 
circumstances, GC4419/placebo should not be administered on that day.  Breaks in IMRT will be 
determined by the patient’s treating physician in accordance with standard of care. Patients 
should resume GC4419/placebo administration when IMRT resumes.  On days when planned 
doses of both GC4419/placebo and IMRT are not administered (e.g., due to a holiday site 
closure, etc.), GC4419/placebo dosing may be extended along with IMRT to make up the missed 
dose(s) up to a maximum of 35 doses of GC4419/placebo.  If a fraction of IMRT is not 


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administered for any reason after GC4419/placebo has been administered, that day’s 
GC4419/placebo will count as one of the 35 doses. 
Anti-emetic prophylaxis and hematopoietic growth factor use should be administered per ASCO 
guidelines.  If institutional guidelines permit, cisplatin may be administered prior to or after the 
first day of IMRT, as long as it follows a weekly or tri-weekly schedule.  On days in which 
chemotherapy and GC4419/placebo are administered, the administration sequence should be 
GC4419/placebo, IMRT, prehydration, and cisplatin if possible. Patients treated with induction 
chemotherapy prior to concomitant chemoradiation are not eligible for this study. 
6.2.1. 
Rationale for GC4419 Dose and Schedule Selection 
Data from the GT-001 trial indicate that the acute toxicity of GC4419 and the overall adverse 
event profile in combination with IMRT/cisplatin are as expected.  GC4419 does not appear to 
increase the toxicity of IMRT/cisplatin.  The acute toxicity of GC4419 was acceptable at all 
doses tested, and consistent with prior expectations as described in the Investigator’s Brochure.  
A true “maximum tolerated dose” of GC4419 by the common definition used in oncology Phase 
1 trials (>1/6 patients with DLT) was not exceeded in the GT-001 trial.  Although dose-limiting 
toxicities were suggested in two patients receiving 112 mg/dose, the relationship of the events to 
GC4419 is questionable in each case.  However, the overall incidence of Grade 3 nausea at 112 
mg was nominally greater than at lower doses.  Even if not strictly dose-limiting, nausea is 
highly undesirable for the indication currently under study.  In addition, circumoral paresthesia, 
although mild, was dose-related.  Therefore, to provide an additional margin of safety and reduce 
the possibility of adverse events that could increase the possibility of breaking study blinding, an 
upper dose of 90 mg of GC4419 will be used in the present trial.  Safety was acceptable at this 
dose when administered for 30-35 doses over six-seven weeks.  Accordingly, the available safety 
data support the doses selected for the present trial for administration daily on weekdays for a 
full course of IMRT. 
Also of note is that Phase 1 data have not indicated a clear dose-response relationship with 
regard to either safety or potential efficacy in preventing OM, although there did appear to be a 
positive relationship between the total duration of GC4419 treatment and the incidence, onset, 
and duration of severe OM.   
The small cohort sizes and overall Phase 1 sample size preclude conclusions about a dose-
response relationship. As a next step in exploring such relationships, Galera will study 30 mg as 
a “low” dose in one of the two active treatment arms in GT-201.   
6.2.2. 
Rationale for Cisplatin/IMRT Treatment Plan 
Meta-analyses have indicated superior survival for HNC patients treated with concurrent 
chemoradiotherapy compared with standard fractionation (M-F) radiation therapy alone.  While 
not all available regimens have been tested directly against one another, the benefit appears 
superior for single-agent cisplatin over other chemotherapy regimens,40 and concurrent IMRT 
plus platinum monotherapy was chosen as one arm of the ongoing RTOG 1016 trial in human 
papilloma virus-associated oropharyngeal cancer.  The other arm of that trial uses IMRT plus 
cetuximab, as a potentially less-toxic, equally efficacious regimen to IMRT/cisplatin, based on 
the results from the trial of Bonner et. al.,8 and other studies.  The incidence of severe OM may 


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be lower when IMRT is combined with cetuximab than with cisplatin; in the Bonner study, 
[NCI-CTCAE] Grade 3-5 OM was reported in 56% of patients receiving IMRT plus cetuximab.  
Survival data for RTOG 1016 are anticipated in 2020.41 For purposes of the GT-201 study, the 
still-standard cisplatin/IMRT regimen has been chosen as it poses a significant medical need by 
virtue of the high incidence of associated severe OM.  In the event that GT-201 yields positive 
results with regard to OM, the combination of GC4419, IMRT, and cetuximab may be studied in 
a separate, future trial.  It should be noted that RTOG 0522 determined that adding cetuximab to 
IMRT plus cisplatin did not increase antitumor efficacy, but did increase toxicity.7  
Standard fractionation (five fractions/week, delivered M-F) IMRT has been chosen for the GT-
201 trial.  Although accelerated fractionation (six fractions/week, combined with two rather than 
three doses of cisplatin q3 weeks), has been studied, prospective lead investigators for GT-201 
have advised that standard fractionation remains the widely-used standard, and in the interest of 
using a chemoradiation regimen that is as uniform and commonly-used as possible, the standard 
fractionation approach is being retained.  It is noted that accelerated fractionation appears 
substantially to increase the incidence of severe OM.42   
Galera believes that the q3 weeks cisplatin regimen has not been directly compared with the 
once-weekly cisplatin regimen in combination with IMRT for HNC cancer in a clinical trial.  
These two regimens appear to be used interchangeably based on investigator preference and 
clinical assessment of the risk of cisplatin toxicity to the patient.   The data supporting the 
information in Table 2 includes patients treated with both cisplatin schedules, but these data do 
not indicate a difference in the incidence of severe OM based on the cisplatin schedule used 
(Sonis, personal communication).  However, and on advice of the Division of Oncology of the 
U.S. Food and Drug Administration, enrolled patients will be stratified based on the cisplatin 
regimen to be used. 
6.2.3. 
Rationale for Tumor Follow-up and Analysis 
Although the mechanism of action and existing nonclinical data (in vitro and in vivo) with 
GC4419 uniformly indicate otherwise, there is a theoretical potential for GC4419 to protect the 
tumor from the therapeutic effects of concurrent chemoradiation.  Patient candidates for GT-201 
will be informed of this potential risk and the existing data as part of the consent process and 
document.  There has been no suggestion of tumor protection so far in GT-001 [data not shown].   
Fakhry et.al. have recently published an analysis comparing time to and patterns of progression 
for HPV-positive and HPV-negative patients treated in RTOG 0129 or RTOG 0522.46   The rate 
of progression was similar in the two groups and is summarized in Table 8.  
After a median follow up of four years, the majority of progression events was found to have 
occurred in the first year after protocol therapy, and the vast majority of all progressions 
observed occurred by the end of three years. 
 
 


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Table 8: 
Time to Tumor Progression in RTOG 0129 and RTOG 0522 (Fakhry et.al. -
ref 46) 
 
HPV-positive patients 
HPV-negative patients 
Median time to progression (months) 
8.2 
7.3 
Progression within first year post treatment 
65% 
63% 
Progression within first two years post 
treatment 
82% 
86% 
Progression within first three years post 
treatment 
86% 
93% 
This information suggests that tumor control data at two years after protocol treatment may 
provide a strong initial indication that results are consistent with expectations.  As such, patients 
in this Phase 2 trial will be followed for tumor progression and overall survival for two years 
after completing treatment.   
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Approximately 216 total patients from investigational sites in US and Canada will be enrolled to 
achieve 195 evaluable patients, with 65 evaluable patients per treatment arm.  Patients 
appropriate for this trial will be identified by the Principal Investigator (or designee) who will 
make a preliminary determination of the patient’s eligibility for the trial in accordance with the 
provisions of the study protocol.  Once a patient is enrolled to the study, the Sponsor or designee 
will assign a unique patient identification number that does not contain any Personal Health 
Information that will be used to reference the patient and corresponding data that is collected. 
7.1. 
Subject Inclusion Criteria 
Patients are required to meet the following inclusion criteria before entering the trial: 
1. Pathologically-confirmed diagnosis of squamous cell carcinoma of the head and neck, 
defined as SCC of the oral cavity or oropharynx that will be treated with cisplatin plus 
concurrent IMRT 
Note: Patients with unknown primary tumors whose treatment plan matches the 
requirements specified in Inclusion Criteria 2 and 3 below are eligible for the trial.   
2. Treatment plan to receive a continuous course of IMRT delivered as single daily fractions 
of 2.0 to 2.2 Gy with a cumulative radiation dose between 60 Gy and 72 Gy. Planned 
radiation treatment fields must include at least two oral sites (buccal mucosa, floor of 
mouth, tongue, soft palate) that are each planned to receive a total of ≥50 Gy.  Patients 
who have had prior surgery are eligible, provided they have fully recovered from surgery, 
and patients who may have surgery in the future are eligible. 
Note: Unavoidable doses of at least 50 Gy, to include entrance, exit, and scatter doses, 
still constitutes planned radiation. 
3. Treatment plan to receive standard cisplatin monotherapy administered either every three 
weeks (80-100 mg/m2 for 3 doses) or weekly (30-40 mg/m2 for 6-7 doses). The decision 
on which cisplatin regimen to use in combination with IMRT and GC4419 will be at the 
discretion of the investigator. 
4. Aged 18 years or older 
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
6. Adequate hematologic function as indicated by: 
• Absolute neutrophil counts (ANC) ≥ 1,500/mm3 
• Hemoglobin (Hgb) ≥ 9.0 g/dL 
• Platelet count ≥ 100,000/mm3 
7. Adequate renal and liver function as indicated by: 
• Serum creatinine acceptable for treatment with cisplatin per institutional guidelines 
• Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 


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• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
• Alkaline phosphatase ≤ 2.5 x ULN  
8. Human papilloma virus (HPV) status in tumor has been documented, using tumor 
immunohistochemistry for p16 or other accepted test 
9. Serum pregnancy test negative for females of childbearing potential 
10. Males and females must agree to use effective contraception starting prior to the first day 
of treatment and continuing for 30 days after the last dose of GC4419 
11. Properly obtained written informed consent 
7.2. 
Subject Exclusion Criteria 
Patients will be excluded if they meet any of the following exclusion criteria: 
1. Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands 
2. Metastatic disease (Stage IV C) 
3. Prior radiotherapy to the region of the study cancer or adjacent anatomical sites or more 
than 25% of total body marrow-bearing area (potentially interfering with chemotherapy 
tolerance) 
4. Prior induction chemotherapy 
5. Receiving any approved or investigational anti-cancer agent other than those provided for 
in this study 
6. Concurrent participation in another interventional clinical trial or use of another 
investigational agent within 30 days of study entry 
Note: Patients who are participating in non-interventional clinical trials (e.g., QOL, 
imaging, observational, follow-up studies, etc.) are eligible, regardless of the timing of 
participation. 
7. Requirement for significantly modified diet (liquids and/or nothing by mouth) due to 
compromised oral/pharyngeal function at baseline 
8. Complete reliance on parenteral or gastrointestinal tube-delivered nutrition at baseline  
Note: Patients who have gastrostomy tubes prophylactically placed are eligible. Patients 
receiving supplemental nutrition through a gastrostomy tube at baseline may be eligible 
depending on diet. 
9. Malignant tumors other than HNC within the last five years, unless treated definitively 
and with low risk of recurrence in the judgment of the treating investigator  
10. Active infectious disease excluding oral candidiasis 
11. Presence of oral mucositis (WHO Score ≥ Grade 1) at study entry 
12. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for 
hepatitis B and do not have a history of infection are eligible) 


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13. Female patients who are pregnant or breastfeeding 
14. Known allergies or intolerance to cisplatin and similar platinum-containing compounds 
15. Requirement for concurrent treatment with nitrates or other drugs that may, in the 
judgment of the treating investigator, create a risk for a precipitous decrease in blood 
pressure 
16. Medical history that includes any condition, or requires the use of concomitant 
medications which, in the investigator’s judgment, are associated with or create a risk of 
increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes.   
7.3. 
Rationale for Patient Population 
Eligibility will be limited to patients with squamous cell tumors of the oral cavity or oropharynx 
in an attempt to keep the evaluation of OM as uniform as possible and to facilitate comparison 
with the Phase 1 data and the assumptions derived from the matched data base described in 
Table 2.  Although some trials, such as the trials of palifermin for OM in patients with HNC 
cancer, have included other anatomic sites (e.g., laryngeal, hypopharyngeal), exclusion of these 
from the current trial may simplify the evaluation of OM (e.g., by reducing the need for 
endoscopy) for the immediate goal of obtaining a clearer assessment of the efficacy of GC4419 
in the proposed indication.  Patients with locally advanced squamous cell cancer of the oral 
cavity or oropharynx remain appropriate candidates for concurrent chemoradiation as standard of 
care, with single-agent cisplatin perhaps the most widely accepted and widely used standard 
regimen. 
Eligibility will include patients scheduled to receive the prescribed IMRT/cisplatin regimen 
either as definitive therapy or post-operatively.  Both groups may be candidates for 
IMRT/cisplatin as standard care and the incidence of severe OM is expected to be similar for 
both groups.  In addition, both have been included in the Phase 1 trial, GT-001. 
Patients with unknown primary tumor whose IMRT/cisplatin treatment plans conform to study 
requirements will be eligible, as most of these patients are considered likely to have 
oropharyngeal or oral cavity primary tumors. 
7.4. 
Screen Failures 
A patient is considered to be a screen failure if the patient signs the informed consent form but 
withdraws consent or is deemed ineligible before being randomly assigned to a treatment arm.  
The reason why the patient was precluded from the clinical trial will be collected.  All patients 
who sign the informed consent form for this study, including screening failures, will be listed on 
the Screening, Enrollment, and Discontinuation Log which is further detailed in the Regulatory 
Binder. 
7.5. 
Randomization Failures 
A patient is considered to be a randomization failure if the patient signs the informed consent 
form and is randomized to a treatment arm but withdraws consent or is deemed ineligible prior to 
receiving their first dose of IMRT and GC4419/placebo. Basic demographic and disease history 


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information will be collected for randomization failures, as well of the reason the patient was 
precluded from the clinical trial. All randomization failures will be listed on the Screening, 
Enrollment, and Discontinuation Log which is further detailed in the Regulatory Binder. 
7.6. 
Subject Withdrawal Criteria 
In accordance with the Declaration of Helsinki, a patient has the right to withdraw from the study 
at any time for any reason. The investigator may also, at his/her discretion, discontinue a patient 
from participating in this study at any time.  Additionally, study treatment may be discontinued 
for any of the following reasons: 
• Adverse Event 
• Medical requirement to administer a contra-indicated medication 
• Patient non-compliance 
• Discontinuation of the study at the request of Galera Therapeutics, Inc. 
The primary reason for ceasing treatment with the randomized therapy (GC4419 or placebo) will 
be clearly documented in the patient’s medical record and recorded on the appropriate CRF page.  
Once a patient discontinues, the patient will not be allowed to be retreated. 
If a patient discontinues randomized therapy as a result of an adverse event (AE) or serious 
adverse event (SAE), every attempt should be made to keep the patient in the study and continue 
to perform the required study-related follow-up and procedures.  If this is not possible or 
acceptable to the patient or investigator, the patient may be withdrawn from the study.  
7.7. 
Study and Site Closure 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  Should 
this be necessary, both parties will arrange discontinuation procedures.  In terminating the study, 
Galera Therapeutics, Inc. and the investigator will assure that adequate consideration is given to 
the protection of the patients’ interests. 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or site staff, as appropriate: 
• Return of all study data to Galera Therapeutics, Inc. (as applicable) 
• Resolution of all data queries 
• Accountability, reconciliation, and arrangements for all unused study drug 
• Review of site study records for completeness 
• Shipment of laboratory samples (as applicable) 
In addition, Galera Therapeutics, Inc. reserves the right to temporarily suspend or prematurely 
discontinue this study either at a single site or at all sites 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 investigator 
(including the reasons for taking such action) at that time.  When feasible, Galera Therapeutics, 


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Inc. will provide advance notification to the investigator of the impending action prior to it 
taking effect. 
Galera Therapeutics, Inc. will promptly inform all other investigators and/or institutions 
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 investigator must inform the 
IRB/IEC/REB promptly and provide the reason for the suspension or termination.  If the study is 
prematurely discontinued, all study data must be returned to Galera Therapeutics, Inc. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and Galera Therapeutics, Inc.  


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Concomitant Medications 
All concomitant therapies (e.g., prescription and over-the-counter medications) taken by patients 
from the date of randomization through 30 days following the last GC4419/placebo, IMRT or 
cisplatin (i.e. whichever occurs last) dose will be collected in the CRF.  Additionally, any 
concomitant therapies if used to treat any serious or related adverse event will be recorded in the 
CRF.   
Note that narcotic medications will be captured separately in a pain medication diary and entered 
into a specific segment of the CRF, apart from other concomitant medications. Narcotic use will 
only be recorded from the Baseline Visit through the Last Day of IMRT Visit. 
Anti-emetic prophylaxis and hematopoietic growth factors should be used per ASCO guidelines. 
If a patient withdraws consent for the study or is removed from the study completely (i.e., the 
patient is no longer participating in any study procedures or follow-up) no further data should be 
collected after the date of the patient’s study discontinuation.  
8.1.1. 
Prohibited Medications 
Investigators may prescribe any concomitant medication or supportive therapy deemed necessary 
to provide adequate supportive care including antiemetics, systemic antibiotics, hydration to 
prevent renal damage, topical fluoride etc., with the following exceptions:  
• Low-level laser treatment for OM 
• Amifostine (Ethyol®)   
• Benzydamine (Difflam®) 
• Cetuximab (Erbitux®) 
• Glutamine applied topically  
• GM-CSF applied topically 
• ‘Magic mouthwashes’ or ‘Miracle mouthwashes’ are permitted, provided they do not 
contain:  
o Chlorhexidine  
o Hydrogen peroxide  
o Diphenhydramine (Benadryl®) 
o Tetracycline 
o Any other listed disallowed medications  
o Notes:  
o Topical lidocaine preparations are permitted 


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o Diphenhydramine (Benadryl®) administered as tablets for by injection is 
permitted; only diphenhydramine liquid formulation is prohibited 
• MuGard™, Gelclair®, Episil®, or other barrier devices 
• Caphosol® 
• Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildanefil, tadalafil, or 
similar agents) or other drugs that in the judgment of the treating investigator could 
create a risk of a precipitous decrease in blood pressure are prohibited until at least 24 
hours after the last dose of GC4419 
• Pyridostigmine or other drugs that in the judgment of the treating investigator could 
create a risk of increased carotid sinus sensitivity, symptomatic bradycardia, or 
syncopal episodes  
• Palifermin (Kepivance®) or other keratinocyte or fibroblast growth factor 
• Povidone-iodine rinses  
• Steroid rinses  
• Sucralfate in suspension form (use of sucralfate tablets is not proscribed)  
• Other biologic response modifiers – except systemic hematopoietic growth factors for 
the management of anemia or myelosuppression   
• Concurrent approved or investigational anti-cancer therapy (e.g., chemotherapy, 
immunotherapy, targeted therapy, hormone and biologic therapy) other than the 
Protocol regimen 
• Other investigational agents 
All medication restrictions end after post-IMRT OM follow-up is completed unless otherwise 
noted. 
Patients who receive prohibited medications prior to completion of post-IMRT OM follow-up 
will not automatically be removed from the study; however, administration of a prohibited 
medication is a significant deviation from the protocol and must be reported to the Medical 
Monitor as soon as possible and the presiding IRB/IEC/REB (per institutional guidelines).  The 
decision for study continuation or discontinuation will be made at that time on a case-by-case 
basis and in consideration of the clinical requirement and circumstances.       
A standard oral care regimen is recommended, consisting of aggressive oral hygiene, frequent 
saline rinsing, and the use of daily topical fluoride.  Mouthwashes or rinses containing sodium 
bicarbonate, clotrimazole (Mycelex), nystatin, fluconazole (Diflucan), viscous xylocaine, and/or 
viscous lidocaine are permitted. If a patient uses “Magic Mouthwashes” or “Miracle 
Mouthwashes,” all ingredients must be recorded in the patient’s medical record in order to 
confirm the mouthwashes did not contain the prohibited ingredients listed above. 
Anti-emetic prophylaxis and hematopoietic growth factor use are permitted per ASCO 
guidelines.  Following ASCO (and MASCC) guidelines for the prevention and management of 
chemotherapy-induced nausea and vomiting (CINV) is strongly encouraged. 


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8.2. 
Treatment Compliance 
Compliance with GC4419/placebo dosing, including administration details (e.g., volume, start, 
stop times, etc.) should be documented in the source documents and recorded on the Case Report 
Form (CRF). 
8.3. 
Randomization and Blinding 
8.3.1. 
Treatment Assignment 
Patients will be randomly assigned to one of the three study arms through an interactive voice 
randomization system (IVRS) or web-based randomization system.  The system will assign a 
patient a unique randomization number that will remain consistent for the duration of the study.  
See the Pharmacy Binder for additional information regarding patient randomization and the 
IVRS system.   
8.3.2. 
Stratification 
Central randomization will be stratified according to the following criteria: 
• HPV status at baseline: positive vs. negative 
• Initial chemotherapy schedule: q3 weeks or weekly cisplatin 
8.3.3. 
Blinding 
Treatment should remain blinded until the end of the Post-active Phase of the study.  Only in the 
case of an emergency, when knowledge of the investigational product is essential for the clinical 
management or welfare of the patient, may the investigator unblind a patient’s treatment 
assignment prior to the end of the Post-active Phase.  The investigator will, whenever possible, 
discuss options with the Medical Monitor, on-call physician, or appropriate Galera Therapeutics, 
Inc./CRO study personnel before unblinding.  If the blind is broken for any reason and the 
investigator is unable to contact Galera Therapeutics, Inc. prior to unblinding, the investigator 
must notify Galera Therapeutics, Inc./CRO as soon as possible following the unblinding incident 
without revealing the subject’s study treatment assignment, unless the information is important 
to the safety of patients remaining in the study.  In addition, the investigator will record the date 
and reason for revealing the blinded treatment assignment for that subject in the appropriate 
section of the CRFs. 
If a serious adverse event (SAE; as defined in Section 12.1.2) is reported to Galera Therapeutics, 
Inc./CRO, Galera Therapeutics, Inc. staff may unblind the treatment assignment for the 
individual patient.  If an expedited regulatory report to one or more regulatory agencies is 
required, the report will identify the patient’s treatment assignment.  When applicable, a copy of 
the regulatory report may be sent to investigators in accordance with relevant regulations, Galera 
Therapeutics, Inc. policy, or both. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
GC4419 
GC4419 (manganese,dichloro[(4aS,13aS,17aS,21aS)-
1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21a-eicosahydro-11,7-nitilo-7H-
dibenzo[b,h][1,2,7,10]tetraazacylcoheptadecine-κN5,κN13,κN18,κN21,κN22]-) is a water 
soluble, highly stable, low molecular weight manganese-containing macrocyclic ligand complex 
whose activity mimics that of naturally occurring SOD enzymes. 
GC4419 is formulated as a clear solution at two concentrations to support the active arms: 
• Arm A: 30 mg GC4419: 3 mg/mL in 26 mM sodium bicarbonate-buffered 0.9 wt. % 
saline for parenteral administration.   
• Arm B: 90 mg GC4419: 9 mg/mL in 26 mM sodium bicarbonate-buffered 0.9 wt. % 
saline for parenteral administration.   
There are no other excipients.  GC4419 is packaged as an 11 mL ± 0.1mL aliquot in a 10 mL 
amber glass vial with an S-127 4432/50 gray stopper and a 20 mm red flip-off seal. 
Placebo 
• Arm C: 26 mM sodium bicarbonate-buffered 0.9 wt. % saline for parenteral 
administration. 
There are no other excipients.  Placebo is packaged as a clear solution of 11 mL ± 0.1mL aliquot 
in a 10 mL amber glass vial, with an S-127 4432/50 gray stopper and a 20 mm red flip-off seal. 
9.2. 
Study Drug Packaging and Labeling 
GC4419 (either concentration) and placebo will be presented in kits of 35 single-use vials, which 
represent 35 daily doses to be administered IV concurrent with IMRT.  To maintain the blind, 
each concentration of GC4419, as well as placebo, will be packaged into amber vials and will 
appear generally identical; that is, there will be no distinguishing features in or on the packaging 
that could permit the identification of GC4419 concentration or placebo.   
9.3. 
GC4419 
GC4419 is packaged as an 11 mL ± 0.1mL aliquot in a 10 mL amber glass vial with a S-127 
4432/50 gray stopper and a 20 mm red flip-off seal. Each bottle will be labeled with the 
appropriate language, including the required regulatory text. 
9.4. 
Placebo 
Placebo is packaged as an 11 mL ± 0.1mL aliquot in a 10 mL amber glass vial with an S-127 
4432/50 gray stopper and a 20 mm red flip-off seal. Each bottle will be labeled with the 
appropriate language, including the required regulatory text. 


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9.5. 
Study Drug Storage 
GC4419 and Placebo 
GC4419 solutions must be stored at 2°C to 8°C at all times until use. GC4419 solutions must not 
be frozen at any time. Temperature excursions above freezing and up to 25°C or down to 0.1°C 
for four hours are accepted; however, Galera Therapeutics, Inc. or its designee must be notified 
immediately of the temperature excursion to ensure proper oversight.  
Once prepared, the IV bags containing GC4419/saline mixtures must also be stored at 2°C to 
8°C until use, and must be administered to patients within 24 hours of preparation.  GC4419 
dosing solutions must not be frozen at any time.  If freezing of the material is evident, that supply 
must be quarantined per institutional guidelines and Galera Therapeutics, Inc. or its designee 
must be notified immediately. 
9.6. 
Study Drug Preparation 
GC4419 and Placebo 
GC4419 will be provided to the study site in single use, sterile, pyrogen-free vials ready for dose 
preparation. Proper mixing with normal saline is required. Standard aseptic techniques will be 
used to maintain sterility.  
Assignment of treatment arm will be randomized 1:1:1 with respect to treatment arms A, B and 
C.  GC4419 (either concentration) and placebo will be presented in kits of 35 single-use vials, 
which represent 35 daily doses to be administered IV concurrent with IMRT.   
To prepare daily IV solutions, investigational pharmacists will extract of 10 mL from a single 
vial and add to 250 mL normal saline. Note that there is no extraction of saline (i.e., the infusion 
solution volume will be 250 mL saline + 10mL volume of GC4419/placebo).  No additional 
modifications or adjustments are to be made to the infusion solution.   
Further information and preparation details will be provided in a separate pharmacy manual.   
Note: Investigational staff who prepare infusion solutions cannot be oral evaluators. 
9.7. 
Administration 
GC4419 and Placebo 
GC4419 or Placebo/saline mixture will be administered intravenously at an infusion rate that 
totals 60 min (± 6 min to account for saline overfill) for the total dose assigned. Infusions of 
GC4419/placebo must be administered using an infusion pump (i.e., not by drip rate).  Infusion 
pump models are not specified and may be per institutional preference/standard. 
To facilitate administration of GC4419 according to the study schedule, an indwelling venous 
access device may be used, at the discretion of the treating investigator.  If an indwelling venous 
access device is placed to facilitate administration of GC4419, this fact will be recorded with the 
study data, as will information about the date of placement, type of device, and subsequent 
complications or adverse events related to the use of the device. 


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IMRT must be initiated as soon as possible upon completion of the GC4419/placebo infusion, 
but no later than 60 minutes following the end of the infusion.  
GC4419/placebo will be given beginning on the first day of radiation and continuing daily, 
concurrent with each dose of IMRT, to a cumulative radiation dose of approximately 60-72 Gy. 
Table 9 outlines the chemoradiation and GC4419/placebo administration schedules.  Please note 
chemotherapy is not required to be administered on the study days listed in Table 9 as long as it 
follows a weekly or tri-weekly schedule. 
If IMRT is not administered on any given day due to a treatment break or unforeseen 
circumstances, GC4419/placebo should not be administered on that day.  Breaks in IMRT will be 
determined by the patient’s treating physician in accordance with standard of care. Patients 
should resume GC4419/placebo administration when IMRT resumes.  On days when planned 
doses of both GC4419/placebo and IMRT are not administered (e.g., due to a holiday site 
closure), GC4419/placebo dosing may be extended along with IMRT to make up the missed 
dose(s) to a maximum of 35 doses of GC4419/placebo.  If a fraction of IMRT is not administered 
for any reason after GC4419/placebo has been administered, that day’s GC4419/placebo will 
count as one of the 35 doses. 
Table 9: 
Chemoradiation and GC4419 Example Administration Schedule: 35 Doses of 
GC4419 (7 Week Schedule) 
Treatment 
Week 1 
Week 2 
Week 3 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Days 
6&7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Days 
13&14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Days 
20&21 
GC4419/   
Placebo1 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Cisplatin2 
Tri-Weekly 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Radiation3 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Treatment 
Week 4 
Week 5 
Week 6 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Days 
27&28 
Day 
29 
Day 
30 
Day 
31 
Day 
32 
Day 
33 
Days 
34&35 
Day 
36 
Day 
37 
Day 
38 
Day 
39 
Day 
40 
Days 
41&42 
GC4419/   
Placebo1 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Cisplatin1 
Tri-Weekly 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weekly 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Radiation2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 


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Treatment 
Week 7 
Day 
43 
Day 
44 
Day 
45 
Day 
46 
Day 
47 
Days 
48&49 
GC4419/   
Placebo1 
X 
X 
X 
X 
X 
 
Cisplatin2 
Tri-Weekly 
 
 
 
 
X 
 
Weekly 
X4 
 
 
 
 
 
Radiation3 
X 
X 
X 
X 
X 
 
1 Intravenous GC4419/placebo is administered by a 60-minute intravenous infusion (±6 min) once a day for the first 
35 days of IMRT (Monday through Friday).  IMRT must be initiated as soon as possible upon completion of 
GC4419/placebo infusion, but no later than 60 minutes post GC4419/placebo infusion.  On Day 1/Baseline, 
chemotherapy prehydration and infusion should be administered after GC4419/placebo infusion and IMRT, if 
possible. If IMRT is not received on any given day due to a treatment break or unforeseen circumstances, 
GC4419/placebo should not be administered on that day. Patients should resume GC4419/placebo administration 
when IMRT resumes. If a patient is scheduled to receive IMRT on a weekend day (e.g., to make-up for a holiday 
site closure), the investigator should contact the Medical Monitor for a discussion prior to IMRT administration. 
2 Cisplatin monotherapy should be administered in a standard q3 weeks regimen (80-100 mg/m2) or weekly regimen 
(30-40 mg/m2). Anti-emetic prophylaxis and hematopoietic growth factor use should be administered per ASCO 
guidelines.  If institutional guidelines permit, cisplatin may be administered prior to or after the first day of IMRT.  
On days in which chemotherapy and GC4419/placebo are administered, the administration sequence should be 
GC4419/placebo, IMRT, prehydration, and then cisplatin, if possible. Patients treated with induction 
chemotherapy prior to concomitant chemoradiation are not eligible for this study. 
3 Eligible patients will be scheduled to receive a continuous course IMRT delivered in single daily fractions of 2.0 
to 2.2 Gy, five days per week (Monday through Friday), with a cumulative radiation dose between 60 Gy and 72 
Gy. Planned radiation treatment fields must include at least two oral sites (buccal mucosa, floor of mouth, tongue, 
soft palate) that are each planned to receive > 50 Gy. 
4 The 7th dose of cisplatin will only be administered if the patient is on the 7-dose weekly cisplatin schedule 
(weekly cisplatin schedule may be 6 or 7 doses, depending on investigator choice). 
9.8. 
Study Drug Accountability 
GC4419 and Placebo 
The investigator is responsible for ensuring adequate accountability of all used and unused 
GC4419/placebo.  This includes acknowledgment of receipt of each shipment of 
GC4419/placebo (quantity and condition), patient dispensing records, and quantity of 
GC4419/placebo returned or destroyed.  Dispensing records will document quantities received 
from Galera Therapeutics, Inc. and quantities dispensed to patients, including container number 
or lot number, date dispensed, patient identifier number, patient initials, and the initials of the 
person dispensing the medication.  Any GC4419/placebo that is prepared but not used must also 
be recorded in the dispensing records. 
All GC4419/placebo supplies and associated documentation will be reviewed and verified by the 
study monitor.  All GC4419/placebo and used containers are to be retained by the site until 
notified by the study monitor, who will instruct the site in the disposal and/or destruction of all 
used GC4419/placebo supplies.  Copies of all forms, documenting drug receipt at the study site, 
drug transportation to satellite sites, and drug return to Galera Therapeutics, Inc., together with 


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drug accountability records, will be retained according to the regulations governing record 
retention. 
The investigator will not allow GC4419/placebo to be given to any patient not included in the 
study or any unauthorized person. 
9.9. 
Study Drug Handling and Disposal 
GC4419 and Placebo 
After completion of the study, all unused study drug will be inventoried and if possible, 
destroyed locally at the site.  GC4419/placebo should not be returned directly to Galera 
Therapeutics, Inc. unless specifically requested by Galera Therapeutics, Inc.  The study monitor 
will instruct the site in the disposal and/or destruction of all used and unused GC4419/placebo 
supplies.  Destruction of any GC4419/placebo should be documented appropriately. 


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10. 
TOXICITY MANAGEMENT 
10.1. 
Dose Delays and Dose Modifications for Toxicity 
The following toxicities require a 25% dose reduction in GC4419/placebo: 
• Grade 3 flushing 
• Grade 2 or greater hypotension within two hours after the start of GC4419/PBO 
infusion 
• Grade 3 or 4 infusion reaction with GC4419 
• Grade 4 vomiting despite optimal antiemetic therapy per current ASCO and MASCC 
guidelines  
Two dose reductions for toxicity will be permitted per patient. After the first event, the patient 
will be re-challenged at 75% of the original dose (7.5 mL GC4419/placebo in 250 mL normal 
saline). After the second event, the patient will be re-challenged at 50% of the original dose (5.0 
mL GC4419/placebo in 250 mL normal saline). Patients who are unable to tolerate 
GC4419/placebo infusions following two dose reductions must be discontinued from the study 
treatment but may continue with cisplatin/IMRT at the discretion of the treating investigator. 
For other toxicities (including those attributable to cisplatin and IMRT), management will be per 
institutional and ASCO guidelines and investigator judgment. 
Galera strongly recommends that treatment modifications for cisplatin related toxicities should 
be managed by reducing the dose and/or altering the schedule of cisplatin administration.  Such 
modifications may be made per the judgment of the treating investigator.  However, substitution 
of other systemic agents (e.g., carboplatin with or without paclitaxel, cetuximab, etc.) is not 
consistent with the protocol and should not be done without prior consultation with the Galera 
Medical Monitor to determine the patient’s eligibility for continuing protocol treatment. 
10.2. 
Supportive Care Guidelines 
Necessary supportive measures for optimal medical care will be given throughout the study.  
Supportive care medications may be administered at the investigator's discretion and recorded in 
the CRF (including administration of prophylactic antiemetic medication if deemed appropriate 
by the investigator).  However, medications are subject to the exclusions listed in Section 8.1.1. 
10.2.1. 
Supportive care for chemotherapy-induced nausea and vomiting (CINV) 
Medication to prevent or manage chemotherapy-induced nausea and vomiting (CINV) should 
follow recent guidelines from ASCO and MASCC (Appendix 7, Section 25).  It should be noted 
that single-agent IV cisplatin is considered a “high risk” treatment for the purposes of these 
guidelines.  Therefore, the use not only of a 5-HT3 receptor antagonist and dexamethasone, but 
also an NK1 antagonist (aprepitant or fosaprepitant) is recommended. 
Supportive care for CINV should be optimized, per ASCO and MASCC guidelines, before 
GC4419 dose is reduced for nausea and vomiting.   


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11. 
ASSESSMENTS 
The study procedures to be conducted for each patient enrolled in the study are described in the 
text that follows and presented in Section 19. 
Any deviation from protocol procedures should be explained in the source documents.  The 
sponsor (or designee) and the site’s institutional review board (IRB – as required by the IRB’s 
policies and procedures) should be notified as soon as possible of any substantial deviations 
potentially affecting patient safety, study drug administration or the assessment of safety, 
efficacy and tolerability parameters. 
11.1. 
Safety Assessments 
Safety will be assessed on the basis of treatment-emergent AEs, physical examination findings, 
clinical laboratory tests, electrocardiogram (ECG) measurements, and vital sign measurements. 
11.1.1. 
Clinical Assessments 
The following clinical assessments are defined when referenced in the schedule of events for this 
study: 
• 12-Lead ECG: ventricular rate, P-R interval, QRS interval, QT interval, and QTc 
• Vital signs: measured following two minutes of rest in the sitting position – 
temperature, systolic and diastolic blood pressures, heart rate and respiration rate  
• Weight and Height: measured in kilograms (kg) and centimeters (cm), respectively 
• Performance Status: ECOG (see Section 22 for conversion criteria for Karnofsky to 
ECOG) 
11.1.2. 
Laboratory Assessments 
All protocol required clinical laboratory assessments should be performed at the central 
laboratory.     
The investigator must assess all abnormal clinical laboratory results for clinical significance in a 
timely fashion. A notation of clinically significant (CS) or non-clinically significant (NCS) with 
initials and date will be documented on the respective laboratory report next to any abnormal 
value.  Information on laboratory AE reporting can be found in Section 12.  
The following laboratory assessments are defined when referenced in the schedule of events for 
this study: 
• Hematology Profile:  hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, and platelet count.  Differential to include total neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils. 
• Serum Chemistry Profile:  glucose, BUN, creatinine, sodium, potassium, calcium, 
albumin, total protein, direct bilirubin, total bilirubin, alkaline phosphatase, ALT 
(SGPT), AST (SGOT), chloride, phosphate, bicarbonate. 
• Serum Pregnancy Test:  required for all females of childbearing potential.  Lack of 
childbearing potential must be noted in the source documents, if applicable. 


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11.2. 
Oral Mucositis Assessments 
OM assessments will be completed at the Screening Visit (within 28 days of IMRT start), 
Baseline Visit, and twice weekly (no less than 48 hours apart) within each five-day IMRT 
treatment period. The extent of patients’ OM will be assessed by a trained evaluator and scored 
using the WHO OM toxicity grading scale.  All patients must have an oral assessment on the last 
day of IMRT treatment.  If a patient withdraws for any reason prior to the end of IMRT, a 
complete oral assessment should be done on that day.  
If a patient has a WHO score ≥ 2 at the completion of IMRT, the patient will be evaluated at 
weekly (± 2 days) intervals until the WHO score returns to ≤ 1 or until the Week 8 Post-IMRT 
Follow-up Visit, whichever comes first.  Post-IMRT Follow-up Visit should occur at intervals of 
7 ± 2 calendar days from the last day of IMRT (i.e., 7, 14, 21 days, etc.) and not 7 days from the 
previous Post-IMRT OM Visit. 
Study site personnel will be provided with specific training and instructions regarding OM 
assessment performance, grading, and documentation.  Designated trained study staff (oral 
evaluators) will conduct all assessments using a standardized and consistent method.  To reduce 
inter-observer variability, the fewest possible number of evaluators should be involved in the 
assessments of each patient.  The oral evaluators will use a Sponsor-provided headlamp for all 
oral assessments conducted for this study.   
The WHO scale will be the measure for assessing OM.  The assessment of the impact of OM on 
a patient’s ability to eat is critical for accurate scoring of the WHO scale.  Therefore, 
standardization of the assessment is very important.  In order to reduce variability in assessing 
food intake, the definitions for solids, liquids, and nothing by mouth are provided here: 
• Solid foods are defined as foods that need to be chewed.  Examples include meat, 
grains and vegetables. 
• Liquids are defined as foods that take the shape of their container.  Examples include 
fruit juices, soups, pureed foods, mashed potatoes, cooked cereals (oatmeal), baby 
food, Jell O®, pudding, and ice cream. 
• Nothing by mouth is defined as no eating or drinking, except enough liquid to allow 
for taking medications. 
The WHO scoring scale is appended in Section 20.  
11.3. 
Radiation Therapy Quality Assurance 
Quality assurance for IMRT will be conducted by a prospective review of the overall treatment 
plan, at the time of patient screening, by a radiation oncologist who is not an investigator on the 
trial.  In addition to IMRT treatment, dosimetry and dose volume histograms will be collected 
after simulation.  Confirmation of appropriate planned doses to oral cavity and oropharynx sub-
sites for eligibility will be confirmed.  Galera plans to collect the following information from all 
investigators: 


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• Institutional policy/radiation oncologists plan regarding the margins used to 
determine Gross Tumor Volumes, (GTV), Clinical Target Volumes (CTV) and 
Planning Target Volumes (PTV) 
• What elective volumes are to be treated 
• What nodal levels are to be treated 
This information will be available for summary and retrospective analysis at the end of the study. 
11.4. 
Patient Reported Outcomes (PRO) 
11.4.1. 
Oral Mucositis Daily Questionnaire (OMDQ) 
Patients will be required to personally complete the OMDQ. The OMDQ will be contained in the 
patient diary and will be completed daily, including weekend days, during the IMRT treatment 
period.  If a patient is required to continue weekly visits after the last day of IMRT based on 
his/her WHO score, the OMDQ will be completed at the time of those visits. As any 
manipulation of the patient’s mouth may influence PRO responses, the OMDQ must be 
completed prior to the oral assessment. 
The mouth and throat soreness (MTS) question of the OMDQ contains five response categories 
from 0 (no soreness) to 4 (extreme soreness). In a study conducted by Stiff et al. (2006), the 
OMDQ MTS question two score was found to be highly correlated with the WHO Scale and 
patients reported the onset, peak and resolution of oral pain one to three days earlier than 
physicians using the clinical assessment.  
The OMDQ has been used in the Phase 1 trial, GT-001, with excellent patient compliance.  The 
OMDQ was used in past trials in OM, notably the registration trial of palifermin.44  In that trial, 
there was high patient compliance (>80%), and good test-retest and internal consistency 
reliability.  Changes in MTS-related scores—particularly for question two (“During the last 24 
hours, how much mouth and throat soreness did you have?”) paralleled changes in the WHO OM 
score and were higher in patients with severe (Grade 3-4) OM than for patients with Grade 1-2 
OM.  Changes in MTS-related scores on the OMDQ preceded changes in the WHO scoring by 
one to two days, perhaps reflecting the timing of visits to assess and record the WHO score. 
It may be further noted that a weekly counterpart to the OMDQ—the OMWQ—has been 
reported to be more responsive to early changes in symptoms than less symptom-focused 
instruments such as the FACT-HN and the FHNSI.45 
The OMDQ can be found in Appendix 3, Section 21.  Results from the OMDQ are an 
exploratory endpoint of this study. 
11.5. 
Health and Economic Outcomes 
Several health and economic outcomes, including the incidence and duration of opioid use, 
insertion of and need for use of gastrostomy tube feedings, use and complications of indwelling 
venous access catheters, and unplanned office visits, emergency room visits, or hospitalizations, 
will be assessed throughout the study.   


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11.5.1. 
Pain Medication Diary 
Questions regarding analgesic use will be contained in the patient pain medication diary, which 
will be completed daily, including weekend days, during the IMRT treatment period (Baseline 
Visit through Last Day of IMRT Visit). In addition, general concomitant medications will be 
recorded by study personnel on weekdays during IMRT treatment. To measure opiate analgesic 
use for oral pain, patients will be required to record in the pain medication diary each time any 
opiate analgesics are administered (either by self or investigational staff).        
Unaided written completion of the pain medication diary by the patient should always be 
encouraged and should be considered the standard method of data collection for the study.  
However, diary responses should be recorded using one or more of the methods described below 
if the patient is unable to fully complete the diary him/herself: 
1. From the patient in the form of a verbal response recorded in the diary with the assistance 
of: 
a. A spouse, family member, or other personal caretaker 
b. Study coordinator, study nurse, or investigator 
2. From the patient’s medical record if: 
a. The patient is hospitalized, or otherwise incapacitated 
b. The patient supplies incomplete information 
Adequate documentation (i.e. emergency room or inpatient hospitalization reports, 
documentation of a prescription on file, etc.) must be on file in the patient’s medical record and 
available for review by the site monitor. 
11.6. 
Pharmacokinetic (PK) Measurements 
Sparse PK sampling will be sought from all patients for GC4419 and its two metabolites, 
GC4520 and GC4570.   
Plasma samples for GC4419 PK measurements will be collected in two cycles: Study Days 1 and 
2, and Study Days 22 and 23.  On Study Days 1 and 22, four samples will be drawn as follows: 
1. The first sample will be drawn prior to GC4419 administration. 
2. The second sample will be drawn within 10 minutes after the end of GC4419 infusion. 
3. The third sample will be drawn within 10 minutes after the end of IMRT.  
4. The fourth and final sample will be drawn between 60 and 180 minutes after the end of 
GC4419 infusion.  If cisplatin is being administered on the same day as PK sampling, it is 
preferred that the PK sample be drawn prior to cisplatin administration, but not required.  
On Study Days 2 and 23 only one PK sample will be drawn.  This sample should be drawn 
approximately 24 hours after the previous day’s GC4419 infusion but prior to the GC4419 
infusion on Days 2 and 23. 
Table 10 below summarizes the PK sample collection time points. Note that this schedule may 
be adjusted to accommodate mid/late-week study starts and holidays. Adjustments in the PK 
schedule must be approved by Galera, and will not be considered a protocol deviation by the 


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Sponsor if pre-approved. Time of actual blood draws for PK assessment must be recorded in the 
source notes.  Plasma PK samples will be sent to a central laboratory for analysis and 
interpretation.  Further details on PK sample collection, processing, and shipping are provided in 
a separate manual. Volumes and start/stop times for administration of IV fluids will be collected 
on PK sampling days. 
Table 10: 
Pharmacokinetic Sampling Schedule to Assess GC4419, Metabolites GC4570 
and GC4520 
 
Day 1 
Day 2 
Day 22 
Day 23 
Pre-GC4419 
X 
X1 
X 
X1 
End of Infusion-GC4419 (+10min) 
X 
 
X 
 
Post-IMRT (+10min) 
X 
 
X 
 
60 – 180 min Post End of Infusion-GC44192 
X 
 
X 
 
1Approximately 24 hours after previous day’s GC4419 infusion. 
2If cisplatin is being administered on this day, it is preferred that the PK sample be drawn prior to cisplatin 
administration, but not required.  
11.7. 
Biological Surrogate Markers of Mucositis 
Preliminary data obtained during the ongoing Phase 1 study provide preliminary evidence of 
GC4419’s   biological activity.  Consequently, biological surrogate markers of mucositis will be 
assessed in all patients enrolled in the study. Correlation between levels of circulating cytokines 
and proteins and clinical endpoints will be assessed by analysis of blood samples collected for all 
patients during the active phase of the study. Refer to Appendix 1, Section 19 for the schedule of 
biomarker assessments for each treatment schedule.  For patients who consent separately, RNA 
samples for the assessment of gene expression patterns prior to receiving the first dose of 
GC4419 and upon completion of GC4419 doses will be collected during screening and on the 
last day of IMRT. Additional details regarding the processing and handling of biomarker samples 
will be provided in a separate manual. 
Whenever possible, blood draws for cytokine analysis should be conducted at OM Visit 2 for 
each protocol-specified week. However, if blood draws must be taken on another day within a 
given week, it will not be considered a protocol deviation. 
11.8. 
Tumor Status Assessment 
11.8.1. 
Clinical Tumor Assessment 
The patient’s tumor status will be assessed clinically at the following time points: 
• Last day of IMRT 
• Every 3 months, ± 30 days, throughout the 1st year post-IMRT (Months 3, 6, 9, and 12) 
• Every 4 months, ± 30 days, throughout the 2nd year post-IMRT (Months 16, 20, and 24) 
The following tumor status information will be collected at each of the above time points: 
• Survival 


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• Disease progression 
• Development of second primary tumors 
• Additional malignancies  
If disease progression is suspected at any of the above visits, a laryngopharyngoscopy (mirror 
and/or fiberoptic and/or direct procedure), should be conducted. If disease progression is not 
suspected, a neck and oral exam is sufficient. 
11.8.2. 
Tumor Imaging 
11.8.2.1. Pre-Treatment Tumor Imaging 
Radiographic tumor imaging must occur within 60 days prior to the first day of IMRT 
(Baseline). One of the following imaging combinations is recommended: 
• CT scan of the neck with contrast plus chest CT with or without contrast 
• MRI scan of the neck with contrast plus chest CT with or without contrast 
• CT scan of the neck with contrast plus PET/CT of the neck and chest with or without 
contrast 
• MRI scan of the neck with contrast plus PET/CT of the neck and chest with or 
without contrast 
If the patient has no evidence of disease at Baseline, it should be clearly indicated. 
11.8.2.2. Post-Treatment Tumor Imaging 
Radiographic imaging must be performed at Months 12 and 24 Post-IMRT for all patients. 
Patients treated definitively (as opposed to post-operatively) will also undergo imaging at Month 
3 Post-IMRT to assess tumor response/clearance to the degree possible. 
Radiographic imaging is highly recommended at any Post-IMRT follow-up visit at which disease 
progression is suspected by the treating physician. If radiographic imaging is performed, both 
local/regional recurrence and distant metastases should be evaluated. 
When possible, the same imaging technique (i.e., CAT, PET, or MRI) that was used for pre-
treatment tumor imaging at the time of staging should be used for post-treatment tumor imaging.  
11.9. 
Xerostomia and Trismus Assessments 
To assess trismus, the maximum opening of the mouth that a patient can achieve will be assessed 
by measuring the distance in millimeters between the incisal edges of the mandibular and 
maxillary incisors at midline using a Sponsor-provided ruler.  
To assess xerostomia, patients will mark their response on a 100 mm visual analog scale (VAS 
See Section 24) anchored on the left with negative responses (very dry; extremely 
uncomfortable; very difficult) and on the right with positive responses (not dry; comfortable; 
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The assessments for trismus and xerostomia will be performed and recorded at Baseline and at 
Months 3, 6, 9, 12, 16, 20, and 24 Post-IMRT. 
11.10. 
Schedule of Time and Events 
A schedule of study assessments table is located in Appendix 1, Section 19.  Minor changes to 
the assessment schedule may be made to accommodate holidays, administrative closures, etc., 
which if necessary, are not considered as significant deviations by the Sponsor.  Sites should 
contact the Sponsor (or its representative) prospectively to address rescheduling protocol 
assessments and data handling. 
11.11. 
Screening Phase 
The following screening observations and procedures will be completed within 28 days of IMRT 
and GC4419 start:  
• Confirm patient eligibility by reviewing inclusion/exclusion criteria 
• Obtain a signed IRB/IEC/REB-approved informed consent  
• Obtain medical history, smoking and alcohol use 
• Obtain HNC history; HNC history should include: 
o HPV status and strain (s) if known 
o Pre-treatment tumor imaging (See Section 11.8.2.1; may be completed within 
60 days prior to the first day of IMRT)   
o Prior treatments  
o Confirmation of histopathological diagnosis of SCC 
• Conduct a complete physical examination, including height 
• Ensure a dental examination was conducted for IMRT clearance and potential sources 
of mucosal irritation (e.g., tooth extraction) were eliminated. The dental exam must 
occur within the 28-day screening period. The exam must be performed by a licensed 
clinician, but not necessarily by a dentist. For edentulous patients, the patient must be 
cleared for IMRT per SOC (i.e., oral exam). 
• Conduct OM assessment and record the WHO score 
• Record planned IMRT and chemotherapy parameters  
• Measure vital signs, body weight, and ECOG Performance Status 
• Conduct a 12-lead ECG 
• Record concomitant medications from date of randomization 
• Record adverse events from date of randomization 
• Record/update medical conditions and illnesses that have occurred since the patient 
signed the ICF 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 


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o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7  
and 19) 
o For patients who consent separately: RNA sample (PAXgene) for genomic 
studies (See Sections 11.7 and 19)  
o Serum pregnancy test for women of childbearing potential 
All questions related to patient eligibility should be directed to Galera’s Medical Monitor or 
designee. 
11.12. 
Active Phase 
11.12.1. 
Baseline/Day 1 (First Day of IMRT and GC4419) 
Prior to receiving the first dose of GC4419 the following observations and procedures will be 
conducted for all patients: 
• Confirm continued patient eligibility by reviewing inclusion/exclusion criteria  
• Measure vital signs, body weight, and ECOG Performance Status 
• Conduct 12-lead ECG  
• Provide and review instructions for completion of the daily diary (OMDQ & 
analgesic recording) 
• Provide the daily diary for recording the OMDQ  
• Have the patient complete the OMDQ and review completion 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Conduct trismus assessment  
• Conduct xerostomia assessment 
• Record BSA (used to confirm cisplatin dosing) 
• Ensure concomitant medications have been recorded from date of randomization  
• Ensure adverse events have been recorded from date of randomization 
• Record placement of an indwelling venous catheter (at baseline, or at any time during 
the study) 
• Record use and/or placement of gastrostomy tube 
• Record/update medical conditions and illnesses that have occurred since the patient 
signed the ICF  
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
o PK sampling (See Section 11.6 and Table 10) 
o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7 
and 19) 


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Administer the first GC4419 dose by continuous intravenous infusion over 60 minutes. IMRT 
must begin as soon as possible but no later than 60 minutes following the end of GC4419 dosing. 
Following IMRT, hydration and chemotherapy pre-medications should be administered per 
institutional guidelines prior to cisplatin administration.    
11.12.2. 
Day 2 of IMRT and GC4419 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed  
• PK sampling (Section 11.6 and Table 10) 
Administer the second GC4419 dose by continuous intravenous infusion. IMRT must begin as 
soon as possible but no later than 60 minutes following the end of GC4419 dosing.    
11.12.3. 
Days 3 to 5 of IMRT and GC4419  
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on Days 3, 4, and 5 unless otherwise noted: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on Day 3, 4, or 5 unless otherwise noted: 
• Conduct second OM assessment for the week (OMDQ must be completed prior to the 
OM assessment) and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Draw blood for laboratory measurements  
o Chemistry profile 
o Hematology profile  
Administer GC4419 dose by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.4. 
Week 2 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 


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• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients once this week: 
• For patients receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
Prior to GC4419 administration the following observations and procedures will be conducted on 
the day of the second OM assessment only: 
• Draw blood for laboratory measurements 
o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7 
and 19) 
Administer GC4419 dose by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.5. 
Week 3 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 


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• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients once this week:  
• For patients receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
Administer GC4419 doses by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.6. 
Week 4 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients once this week: 
• Perform symptom-directed PE 
• Measure vital signs, body weight, and ECOG Performance Status 
• Record BSA (used to confirm chemotherapy dosing) 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on the day of the second OM assessment only: 
• Draw blood for laboratory measurements 


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o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7 
and 19) 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on Days 22 and 23 only:  
• Draw blood for laboratory measurements 
o PK sampling (Section 11.6 and Table 10) 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on Day 22 only:  
• Conduct 12-lead ECG 
Administer GC4419 doses by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.7. 
Week 5 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all patients once this week:  
• For patients receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
Administer GC4419 doses by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 


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11.12.8. 
Week 6 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on the once this week: 
• For patients receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on the day of the second OM assessment only this week: 
• Draw blood for laboratory measurements 
o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7 
and 19) 
Administer GC4419 doses by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.9. 
Week 7 (plus additional IMRT weeks, if needed) 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on all IMRT days: 
• Record concomitant medications 
• Record adverse events 
• Ensure the daily diary is completed; on Friday provide daily diary pages for the 
patient to complete at home over the weekend 


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Prior to IMRT administration the following observations and procedures will be conducted for 
all patients twice during this week, at least 48 hours apart: 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record use and/or placement of gastrostomy tube 
• Record unscheduled office visits, ER visits, or hospitalizations 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients once this week: 
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
• Measure vital signs, body weight, and ECOG Performance Status 
• If receiving cisplatin this week, record BSA (used to confirm cisplatin dosing) 
Administer GC4419 doses by continuous intravenous infusion. IMRT must begin as soon as 
possible but no later than 60 minutes following the end of GC4419 dosing. 
11.12.10. Last Day of IMRT or Early Termination Visit 
Prior to IMRT administration the following observations and procedures will be conducted for 
all patients on the last day of IMRT or if the patient terminates study participation early: 
• Conduct a complete physical examination  
• Measure vital signs, body weight, and ECOG status 
• Conduct clinical tumor status assessment  
• Conduct 12-lead electrocardiogram (ECG) 
• Ensure the daily diary is completed 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score 
• Record any concomitant medications  
• Record adverse events 
• Record use and/or placement of gastrostomy tube    
• Draw blood for laboratory measurements 
o Chemistry profile 
o Hematology profile 
▪ Note: If safety labs have already been drawn during the study week in 
which the last day of IMRT or early termination visit falls, then lab 


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safety tests (chemistry and hematology profiles) do not need to be 
conducted on the last day of IMRT or at the early termination visit.  If 
safety labs have not been drawn during the current study week at the 
time of the early termination visit or on the last day of IMRT, then 
safety labs should be drawn on that day.  Safety labs only need to be 
drawn once per study week after Week 1. 
o Biomarker sample for pro-inflammatory cytokine analysis (See Sections 11.7 
and 19) 
o For patients who consent separately: RNA sample (PAXgene) for genomic 
studies (See Sections 11.7 and 19) 
11.12.11. Post-IMRT Weeks 1 through 8 
If a patient has a WHO score ≥ 2 at the completion of IMRT, the patient will be evaluated at 
weekly (± 2 days) intervals until the WHO score returns to ≤ 1 or until the Week 8 Post-IMRT 
Follow-up Visit, whichever comes first.  Post-IMRT Follow-up Visit should occur at intervals of 
7 ± 2 calendar days from the last day of IMRT (i.e., 7, 14, 21 days, etc.) and not 7 days from the 
previous Post-IMRT Visit.  At each visit, the following should be completed: 
• Administer the OMDQ 
• Conduct OM assessment (OMDQ must be completed prior to the OM assessment) 
and record the severity using the WHO score  
• Record adverse events and concomitant medications through 30 days following the 
last dose of IMRT, cisplatin, or GC4419/placebo (i.e., whichever occurs last) 
11.13. 
Post-Active Phase  
All patients will be followed for two years Post-IMRT. Patients will be seen every 3 months 
throughout the first year Post-IMRT (Months 3, 6, 9, and 12) and every 4 months throughout the 
second year Post-IMRT (Months 16, 20, and 24), ± 30 days for each visit. At each of these visits 
the patient should be seen by a Radiation Oncologist, Medical Oncologist, ENT, or Head & Neck 
Surgeon and the following assessments should be conducted: 
• Clinical tumor assessment (See Section 11.8.1) 
• Xerostomia and Trismus assessments (See Section 11.9)    
Radiographic imaging must be performed at Months 12 and 24 Post-IMRT for all patients. 
Patients treated definitively (as opposed to post-operatively) will also undergo imaging at Month 
3 Post-IMRT to assess tumor response/clearance to the degree possible. 
As indicated in Section 11.8.2.2, radiographic imaging is highly recommended if disease 
progression is suspected by the treating physician at any of the above time points. If radiographic 
imaging is performed, both local/regional recurrence and distant metastases should be evaluated. 
Biopsy of any lesion(s) suspicious for tumor recurrence is also recommended. 
When possible, the same imaging technique (i.e., CAT, PET, or MRI) that was used for pre-
treatment tumor imaging at the time of staging should be used for post-treatment tumor imaging. 


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12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  Throughout the study, AEs will be 
recorded in the source documents and on the appropriate pages of the CRF regardless of whether 
the AEs are considered related to GC4419/placebo.  To avoid confusion, the AE should be 
recorded in standard medical terminology. 
12.1. 
Definitions 
The following definitions of terms are guided by the International Conference on Harmonization 
and the US Code of Federal Regulations and are included here verbatim.   
12.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Examples of an AE include: 
• Significant or unexpected worsening or exacerbation of the condition/indication under 
study.   
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity (grade) of the condition. 
• New conditions detected or diagnosed after investigational product administration even 
though they may have been present prior to the start of the study. 
• Signs, symptoms, or the clinical sequelae associated with a suspected interaction of the 
investigational product with a concomitant medication. 
• Signs, symptoms, or the clinical sequelae associated with a suspected overdose of either 
investigational product or a concurrent medication. 
12.1.2. 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening – NOTE: The term ‘life-threatening’ in the definition of ‘serious’ 
refers to any adverse drug experience [adverse event] that places the patient or 
subject, in the view of the investigator, at immediate risk of death from the reaction as 
it occurred, i.e., it does not include a reaction that, had it occurred in a more severe 
form, might have caused death.  [emphasis added] 


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• Requires inpatient hospitalization or prolongation of hospitalization – NOTE:  In 
general, hospitalization signifies that the patient or subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
• Results in persistent or significant disability/incapacity – NOTE: The term disability 
means a substantial disruption of a person’s ability to conduct normal life functions. 
OR 
• Is a congenital abnormality/birth defect. 
12.2. 
Adverse Event Reporting Requirements 
12.2.1. 
Serious Adverse Events 
All events meeting the criteria for Serious Adverse Events (see Section 12.1.2) must be reported 
by investigational sites within 24-hours of becoming aware of the event.  In order to determine 
the sponsor’s timeline for notifying regulatory authorities and investigators per Federal 
Regulations, an event term, serious criteria, and causality is required at the time of the initial 
report.  Specific SAE reporting instructions are provided in a separate manual. 
The investigator is responsible for notifying the IRB/IEC/REB in writing of serious events as 
soon as is practical in accordance with the policy of the IRB/IEC/REB. 
12.2.2. 
All Adverse Events (AEs) Regardless of Seriousness 
Any adverse medical condition or laboratory abnormality with an onset date before the date of 
randomization is considered to be pre-existing in nature, and part of a patient’s medical history.  
Adverse medical conditions that begin on or after date of randomization will be considered an 
adverse event, including SAEs, and followed for 30 days after the last dose of IMRT, cisplatin, 
or GC4419/placebo (i.e., whichever occurs last), hereafter referred to as the “30 Day Follow-up 
Period”.  Similarly, new events will be reported as AEs/SAEs if the start date is within 30 Day 
Follow-up Period.  Increases in toxicity grade of pre-existing conditions that occur on or after the 
date of randomization are also considered an adverse event. 
All adverse events must be recorded in the patient’s source documents and on the CRF 
regardless of frequency, severity (grade) or assessed relationship to randomized therapy.  
12.2.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more severe than 


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expected for the patient’s condition, or that are present or detected at the time of randomization 
and do not worsen, will not be reported as AEs or SAEs.   
Laboratory abnormalities should only be recorded in the Adverse Event section of the CRF if at 
least one of the following criteria is met: 
• Meets the criteria of an SAE 
• Resulted in a dose reduction and/or delay in the administration of GC4419/placebo, 
IMRT, and/or cisplatin 
• Treatment is initiated for the abnormality 
• Investigational product was discontinued 
• Grade 3 or Grade 4 per National Cancer Institute Common Terminology Criteria for 
Adverse Event Version 4.03 (NCI CTCAE v4.03) 
All other abnormal laboratory findings will be captured via laboratory CRF pages and noted in 
shift tables. 
Abnormal assessments (e.g., ECGs) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definitions as defined in Section 12.1.   
12.2.4. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs 
Oral mucositis and xerostomia will not be reported as AEs as they are captured as study 
endpoints in the CRF.  Progressive disease found by scan or on clinical evaluation should be 
captured on the applicable lesion CRF pages and not as an AE. 
12.2.5. 
Grading of Adverse Events 
The severity of adverse events will be designated as mild, moderate, severe, life threatening, or 
fatal per NCI CTCAE version 4.03. If not specifically addressed in NCI CTCAE version 4.03, 
use Table 11 below: 
Table 11: 
Adverse Event Severity 
Grade  
Criteria1 
Mild – Grade 1 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate – Grade 2 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL2 
Severe – Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL3 
Life Threatening – Grade 4 
Life-threatening consequences; urgent intervention indicated 
Death – Grade 5 
Death related to adverse event 
1 A Semi-colon indicates ‘or’ within the description of the grade. 


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2 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
3 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
12.3. 
Relationship to Study Drug 
All AEs will be categorized by the investigator with respect to their relationship to 
GC4419/placebo. The relationship between GC4419/placebo and the AE may be considered 
related, possibly related, or unrelated. The criteria for each category are listed below: 
• Related: It is likely that GC4419/placebo caused or contributed to the cause of the 
adverse event or laboratory abnormality, when the temporal sequence from the time 
of GC4419/placebo administration, the known consequences of the patient’s 
clinical/state condition or study procedures, the effects of discontinuing or 
reintroducing GC4419/placebo on the adverse event, and other medically relevant 
factors are considered.   
• Possibly Related: There is a reasonable possibility that the adverse event or 
laboratory abnormality was caused by GC4419/placebo, when the temporal sequence 
from the time of GC4419/placebo administration, the known consequences of the 
patient’s clinical state/condition or study procedures, and other medically relevant 
factors are considered.   
• Unrelated: The investigator has a high level of certainty that the patient’s clinical 
state/condition, study procedures, or other medically relevant factors other than 
treatment with GC4419/placebo caused the adverse event or laboratory abnormality.  
This relationship category should only be used when a clear precipitating cause exists 
and it is not reasonably possible that the event is caused by treatment with 
GC4419/placebo. 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possibly related” the event will be considered to be related to the investigational product for the 
purposes of expedited regulatory reporting. 
12.4. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
and provide further information on the patient’s condition. The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE or SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
Non-serious AEs that have not resolved by the end of the 30 Day Follow-up Period will be 
considered ongoing, and marked as such in the CRF.  All SAEs will be followed until they 
resolve or a new baseline is established, at which point the appropriate CRF page(s) or SAE 
Report Form(s) will be updated.   


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Routine collection of AEs will stop at the end of the 30 Day Follow-up Period; however, 
collection of clinical data will continue on AEs of interest or as clinical circumstances warrant 
that exceed the 30 Day Follow-up Period, per below and described in other sections of the 
Protocol: 
• Oral Mucositis: up to 8 weeks post last IMRT dose (Section 11.12.11) 
• Xerostomia and Trismus: through 12 months post last IMRT dose (Section 11.9) 
• Medical events, which in the opinion of the investigator, serious and are believed to 
be a result of study participation to warrant notifying the sponsor (Sections 12.5 and 
12.6).  In these circumstances, the investigator should contact the Galera Medical 
Monitor (or designee) directly to discuss the case, and how it should be reported. 
As reasonably requested by Galera Therapeutics, Inc., the investigator will perform or arrange 
for the conduct of supplemental measurements and/or evaluations to elucidate as fully as 
possible the nature and/or causality of the AE or SAE.  If a patient dies during participation in 
the study or during a recognized follow-up period, Galera Therapeutics, Inc. will be provided 
with a copy of any post-mortem findings, including histopathology. 
12.5. 
Post-Study Reporting Requirements 
Although such information may not be routinely sought or collected by Galera Therapeutics, 
Inc., serious adverse events that occur after the patient has completed a clinical study may be 
reported.  Such cases will be evaluated for expedited reporting. 
12.6. 
Pregnancy 
The risks of treatment with GC4419 during pregnancy have not been evaluated.  Male subjects 
and female subjects of childbearing potential who engage in sexual intercourse should use a 
barrier method of contraception throughout the study and for 30 days following the last dose of 
GC4419/placebo. 
12.6.1. 
Time Period for Collecting Pregnancy Information 
As permitted by IRB/EC/REB policies, any pregnancy that occurs from the first dose of 
GC4419/placebo up to 30 days after last dose should be reported using the appropriate form 
within 2 weeks of learning of the patient’s pregnancy. The patient will be followed throughout 
the course of the pregnancy. Generally, follow-up will be no longer than six to eight weeks 
following the estimated delivery date. Any premature termination of the pregnancy should be 
reported. If a pregnancy is identified outside the 30 days after last dose, the investigator may 
report using clinical judgment.  
12.6.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Patient 
The investigator will attempt to collect pregnancy information on any female partner of a male 
study patient who becomes pregnant while participating in this study.  The investigator will 
record pregnancy information on the appropriate form and submit it to Galera Therapeutics, Inc. 
within 2 weeks of learning of the partner’s pregnancy.  The partner will also be followed to 
determine the outcome of the pregnancy.  Information on the status of the mother and child will 


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be forwarded to Galera Therapeutics, Inc.  Generally, follow-up will be no longer than six to 
eight weeks following the estimated delivery date.  Any premature termination of the pregnancy 
will be reported. If a pregnancy is identified outside the 30 days after last dose, the investigator 
may report using clinical judgment. 
12.7. 
Recording Adverse Events 
All AEs must be recorded on the appropriate CRF regardless of the severity or relationship to 
GC4419/placebo. All AEs that meet the seriousness criteria should also be recorded on the SAE 
Report Form. All SAEs must be reported to the sponsor or delegated organization within the 
timeline stated in Section 12.2. 
The recording of AEs will be based on data obtained from the following sources: 
• Medical and surgical history 
• Physical examinations including vital signs 
• Clinical laboratory test results  
• Patient verbal reports to the investigational staff and documented in the medical chart 
• Patient diary 
All clinical events, including both observed (such as any reaction at sites of application) and 
volunteered problems, complaints, or symptoms, are to be recorded. The need to capture this 
information is not dependent upon whether the clinical event is associated with GC4419/placebo 
use. AEs resulting from concurrent illnesses, reactions to concurrent medications or symptomatic 
progression of disease states are also to be recorded. 
The information to be recorded for AEs will include: 
• The specific type of event in standard medical terminology – diagnosis if known, is 
preferred over symptoms 
• Duration of the clinical event (start and stop dates) 
• Severity (Grade 1, 2, 3, 4, or 5) of the clinical event 
• Seriousness (SAE) criteria, if applicable 
• Relationship of the AE to GC4419/placebo as defined in Section 12.3  
• Management of GC4419/placebo administration and other action taken to alleviate 
the clinical events 
• Clinical outcome of the AE 
If an adverse event changes in grade within the date of randomization through the 30 Day 
Reporting Period, the event should be recorded as a new AE. 
12.8. 
Regulatory Reporting of Adverse Events 
Galera Therapeutics, Inc. will have final determination of reportability and is responsible for 
notifying the relevant regulatory authorities of certain events.  The investigator will report all 


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SAEs that occur at his/her site to the IRB per the site’s IRB regulations. AEs will be reported to 
regulatory authorities in compliance with 21 CFR 312.32, local and regional law and established 
guidance by the Sponsor or its designee. The format of the reports will be dictated by the local 
and regional requirements.  
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical trial.  Each site is responsible for notifying its 
IRB/IEC/REB of these additional SAEs in accordance with local or central IRB/IEC/REB 
procedures.  Copies of each report will be kept in the investigator’s files and adequate 
documentation will be provided to Galera Therapeutics, Inc. including documentation that the 
IRB/IEC/REB was notified of each safety report.  
 
 
 
 


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13. 
STATISTICS 
13.1. 
General Considerations 
A separate Statistical Analysis Plan will provide technical details of the statistical analyses to be 
performed, in addition to the specifications in this protocol. In the event of discrepancies 
between the protocol and the Statistical Analysis Plan, the latter will control the analyses 
performed. 
All statistical analyses will be conducted with the SAS® software package version 9.2 or higher.  
13.1.1. 
Randomization and Stratification 
Eligible patients will be randomized 1:1:1 to the three treatment arms.  Randomization will be 
stratified by: 
1. Tumor human-papilloma virus (HPV) status.  It is now accepted that tumor HPV status is 
a strong independent prognostic factor for survival of patients with oropharyngeal 
cancer,45 and that HPV-positive disease is fundamentally different from HPV-negative 
disease.  HPV-positive oropharyngeal cancer tends to present with early T stage and 
advanced N stage.  Whether the risk of severe OM is different for patients with HPV-
positive disease compared with those with HPV-negative disease has not been 
established; review of the data supporting the information in Table 2 suggests that the 
risks are similar for the two groups (Sonis, personal communication).  However, 
stratification by tumor HPV status is common in trials that are not limited to HPV-
positive disease but include patients with oropharyngeal cancer.  
2. Assigned cisplatin schedule (q3 weeks or weekly). Historical data supporting also do not 
suggest differences in risk of OM based on the cisplatin schedule (q3 weeks or weekly).  
However, based on correspondence with the Food and Drug Administration, patients will 
be stratified by cisplatin schedule in this study.  
It may be noted that the historical data supporting Table 2 also do not suggest a difference in OM 
risk associated with, T stage (although this factor may be co-distributed with HPV status) (Sonis, 
personal communication).  Similarly, whether smoking status affects the risk of OM is not 
certain.  In GT-201, information about smoking (current/past/never, pack-years) will be collected 
and its association with OM assessed in the final data analysis.  However, stratification based on 
T stage, smoking status, or factors other than tumor HPV status and cisplatin schedule is not 
planned. 
13.2. 
Sample Size  
Approximately 216 patients will be enrolled to ensure that 65 patients per arm receive study drug 
and complete their IMRT course, with an assumed proportion of early discontinuations of 10%.    
The primary objective of the study will test the following hypothesis: separately for each active 
arm:  
• H0: the distribution of duration of severe OM in the active arm = the distribution of 
duration of severe OM in the placebo arm  


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• H1: the distribution of duration of severe OM in the active arm ≠ the distribution of 
duration of severe OM in the placebo arm 
Sample size has been calculated using an overall two-sided alpha of 0.05.  
With 65 patients per arm having received GC4419/placebo and completed their IMRT course 
(assumes 72 patients enrolled to each treatment arm with a 10% dropout rate), the study will 
have roughly 80-85% power to detect a reduction in duration in the experimental arm under the 
following assumed incidence of severe OM and percentiles of the distribution of duration of 
severe OM: 
• GC4419 arms: incidence = 40%; duration (25th, 50th, 75th percentile): 0, 0, 21 days  
• Control arm: incidence = 65%; duration (25th, 50th, 75th percentile): 0, 28, 50 days 
13.3. 
Analysis Populations 
The intent-to-treat (ITT) population includes all subjects who are randomized and will be used in 
the primary analysis for all efficacy endpoints. Subjects will be analyzed according to their 
randomized treatment assignments. 
Analyses on other efficacy populations (e,g., a modified intent-to-treat (mITT) population, or an 
“evaluable” or “per protocol” population) may be conducted.  Such analyses will be specified in 
the Statistical Analysis Plan for this study. 
The safety population will include all patients who receive at least one dose of GC4419. Only 
patients with clear documentation that no GC4419 was received may be excluded from analysis. 
Patients will be analyzed according to the dose received.  
13.4. 
Definition of Endpoints 
13.4.1. 
Primary Endpoint 
Duration of severe OM is defined as the number of days from the first occurrence of WHO 
Grade 3 or 4 OM through the first occurrence of non-severe (≤ Grade 2) without a subsequent 
instance of ≥ Grade 3 OM. Subjects with complete study follow-up for severe OM who do not 
develop severe OM will be considered to have durations of 0 days. 
13.4.2. 
Secondary Endpoints 
• Cumulative incidence of severe OM, defined as any occurrence of WHO Grade 3-4 
OM, from the first IMRT fraction through the delivery of the 30th IMRT fraction 
(approximately 60 Gy delivered to tumor)   
• Evaluate and compare the safety of GC4419 at the treatment assignment of each 
respective arm 
• Cumulative incidence of severe OM from the first IMRT fraction through the last 
IMRT fraction   
• Cumulative incidence of Grade 4 OM from the first IMRT fraction through the last 
IMRT fraction   


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• Onset of severe OM: number of IMRT fractions delivered at onset of severe OM  
• Effect of treatment assignment on tumor outcomes (locoregional failure, distant 
metastases, progression-free survival, overall survival)—see also Section 13.9  
13.4.3. 
Exploratory Endpoints 
• Duration of severe OM, excluding those without severe OM (i.e., durations of 0 days) 
• Onset to severe OM, expressed in cumulative IMRT dosage and time (days)  
• Onset to severe OM, expressed as cumulative IMRT dosage, time (days), and number 
of IMRT fractions delivered at onset of severe OM, when excluding those without 
severe OM (i.e., durations of 0 days) 
• Number of instances of severe OM lasting ≥ 7 days, defined as two or more 
consecutive observations of severe OM 
• Cumulative incidence of severe OM from the first IMRT fraction through the end of 
post-IMRT early follow-up; post-IMRT early follow-up will extend for up to eight 
weeks post the last IMRT fraction administered or until a given patient’s OM is WHO 
Grade 0 or 1   
• Cumulative severe OM incidence at cumulative delivery of 20-29, 30-39, 40-49, or 
50-59 Gy of IMRT 
• Duration of Grade 4 OM from the first IMRT fraction through the last IMRT fraction 
• Areas under the OM-severity vs. cumulative IMRT dosage curves 
• Number and percentage of patients with severe OM on more than one visit prior to 
Week 6, Visit 2 
• Total number of days (per patient) of severe OM though the end of IMRT 
• Incidence, onset, and duration of ulcerative (≥ Grade 2) OM 
• Number and duration of delays of IMRT and cisplatin, or of cisplatin dose reductions 
• Other specific toxicities of interest associated with concurrent chemoradiation:   
o Xerostomia (assessed using a five-point Visual Analog Scale of Leveque (see 
Section 24)  
o Trismus, based on measurement of jaw opening 
o Fatigue 
o Weight loss, from serial patient weights in scheduled study visits  
o Radiation dermatitis per NCI-CTCAE v4.03 
o Dysgeusia (changes in taste) per NCI-CTCAE v4.03 
• Scores in individual questions from the Oral Mucositis Daily Questionnaire (OMDQ, 
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• Use of narcotic analgesics by patients according to treatment assignment 
o Percentage of patients using opioid narcotics 
o Time and cumulative IMRT delivered to first opioid narcotic use 
o Median total opioid narcotic dose (morphine equivalents) with 25th-75th 
percentiles 
• Frequency, use, and reasons for use of gastrostomy tubes  
• Frequency, use and complications of indwelling venous access devices 
• Frequency and reasons for unscheduled hospitalizations 
• Levels of selected circulating cytokines (cytokine selection informed by proposed 
GC4419 mechanism of action and Phase 1 results)  
• To assess the effects of treatment assignment on circulating cytokine levels and gene 
expression levels 
13.5. 
Safety Analysis 
Adverse events will be grouped by system organ class, high level term, and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Incidence 
by subject will be tabulated for all treatment emergent, serious, severe, and treatment related 
adverse events. Detailed listings will be provided for all serious adverse events, deaths, and 
withdrawals due to adverse events. 
Laboratory measurements, vital signs, and ECG parameters will be summarized by treatment 
group at each of the protocol specified time points.  
Further details will be provided in the trial’s Statistical Analysis Plan. 
13.6. 
Primary Efficacy Analysis 
Duration will be compared between each active arm and placebo by a van Elteren test, stratified 
by the factors used in randomization, namely baseline HPV status and planned chemotherapy 
schedule.  
Differences in duration will be described by presenting each group’s incidence of severe OM and 
the percentiles of the duration of severe OM, both with and without inclusion of subjects without 
severe OM. 
13.6.1. 
Multiplicity 
To control the overall Type 1 error at 0.05, the testing of each GC4419 dose group to placebo 
will be done sequentially for the primary and secondary endpoints as shown in the following 
table. Testing will proceed conditional on the statistical significance of the prior test(s) at the 
0.05 level. 
 


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Endpoint 
 
Comparison tested at two-sided α = 0.05 
Duration of severe oral mucositis (SOM) 
90 mg versus placebo 
↓ 
30 mg versus placebo 
↓ 
Incidence of SOM through the 30th IMRT 
fraction 
90 mg versus placebo 
↓ 
Incidence of SOM through the end of IMRT 
90 mg versus placebo 
↓ 
Incidence of SOM through the 30th IMRT 
fraction 
30 mg versus placebo 
↓ 
Incidence of SOM through the end of IMRT 
30 mg versus placebo 
↓ 
Incidence of Grade 4 OM through the end of 
IMRT 
90 mg versus placebo 
↓ 
30 mg versus placebo 
↓ 
Onset of SOM expressed as number of IMRT 
fractions at onset 
90 mg versus placebo 
↓ 
30 mg versus placebo 
Under this procedure, duration of severe OM in the 90 mg GC4419 treatment arm will be 
compared with placebo first.  If p≤0.05 for this comparison, duration of severe OM in the 30 mg 
GC4419 treatment arm will be compared.  Additional tests of severe OM incidence or other 
parameters will be performed, sequentially, as long as p≤0.05. If for any test p>0.05, no further 
hypotheses will be formally tested.  
13.6.2. 
Handling of Missing Data 
Investigators should make reasonable attempts to continue to collect WHO OM scores for 
inclusion in the study database for subjects who discontinue from study drug but continue to 
receive further IMRT fractions.  
The trial’s Statistical Analysis Plan will discuss the imputation strategy for subjects who lack 
WHO OM scores, who discontinue from the trial without complete follow-up of WHO OM 
scores, and whose resolution date of severe OM is unknown.  
13.6.3. 
Covariate Adjustment 
Because the trial’s randomization is stratified by baseline HPV status and planned chemotherapy 
schedule, the primary analysis will be stratified by these factors. The Statistical Analysis Plan 
will contain guidelines for combining strata should the size of any of the four strata be 
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13.7. 
Secondary Efficacy Analyses 
13.7.1. 
Cumulative Incidence Endpoints 
Incidence endpoints will be analyzed by Cochran-Mantel-Haenszel tests stratified by the factors 
used in randomization. 
13.7.2. 
Onset of Severe OM: Number of IMRT Fractions Delivered at Onset of Severe 
OM, Time (days), and Cumulative IMRT Delivered at Onset of Severe OM 
Onset of severe OM will be compared using a stratified logrank test, where time is substituted by 
the cumulative IMRT fractions received. Subjects without severe OM will be censored at their 
last IMRT fraction. Kaplan-Meier estimates will be presented in a figure. 
Similar supportive analyses of the endpoint will be performed using days on study and using 
cumulative RT dosage as the unit of time. 
13.8. 
Exploratory Efficacy Analyses 
13.8.1. 
Instances of severe OM lasting ≥ 7 days 
Instances of severe OM lasting seven or more days will be compared by a van Elteran test. The 
proportion of subjects with episodes of severe OM lasting seven or more days will be compared 
by a Cochran-Mantel-Haenszel test. 
Further exploratory efficacy analyses are described in the Statistical Analysis Plan. 
13.9. 
Analysis of Tumor Endpoints 
13.9.1. 
Local or Regional Progression 
Local (primary site) or regional (neck) progression is defined as clinical or radiographic evidence 
of progressive disease at the primary site or neck.  The location of progressive disease should be 
separately distinguished (local vs. neck) if possible.  Progression of local or regional disease 
should be confirmed by biopsy when possible but may be clinically assessed and documented in 
the clinical record at the judgment of the treating clinicians.  Tumor reappearing with the initial 
and immediate adjoining anatomical region of the primary will be considered local recurrence.   
13.9.2. 
Distant Metastasis 
Clear evidence of distant metastases (lung, bone, brain, etc.): biopsy is recommended where 
possible.  Multiple lung nodules/masses are considered distant metastases from the index cancer 
unless proven otherwise.  
The frequencies of locoregional and distant failure will be tabulated and standard Kaplan-Meier 
plots will be made for time-to-event endpoints (OS, PFS, locoregional failure over time, distant 
metastases over time).  Other exploratory analyses of the time-to-event endpoints may also be 
performed; e.g., ratio or difference of t-year event rates, ratio or difference of percentiles of 
survival functions, and ratio or difference of restricted mean survival times or restricted time 
lost.47 


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13.9.3. 
Second Primary Neoplasm 
A solitary, speculated lung mass/nodule is considered a second primary neoplasm unless proven 
otherwise. 
Frequency of second primary neoplasms will be tabulated. 
13.10. 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will perform periodic unblinded safety 
reviews while patients in the trial receive study drug. 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. 
 
   


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
In accordance with International Conference on Harmonisation Good Clinical Practice (ICH-
GCP) guidelines, the study monitor must have direct access to the investigator’s source 
documentation in order to verify the consistency of the data recorded in the electronic CRFs. 
The monitor is responsible for routine review of the electronic CRFs at regular intervals 
throughout the study, to verify adherence to the protocol, and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have full access to any patient 
records needed to verify the entries on the electronic CRFs.  The investigator agrees to cooperate 
with the monitor to assure that any follow-up items identified in the course of these monitoring 
visits are resolved. 
During site visits, the monitor will: 
• Check the progress of the study; 
• Review study data collected; 
• Conduct source document verification; 
• Identify any issues and address their resolution. 
• This will be done in order to verify that the: 
o Data are authentic, accurate, and complete; 
o Safety and rights of subjects are being protected; 
o Study is conducted in accordance with the currently approved protocol (and 
any amendments), GCP, and all applicable regulatory requirements. 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
14.2. 
Audits and Inspections 
Authorized representatives of Galera Therapeutics, Inc., a regulatory authority, an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of a Galera Therapeutics, Inc. audit 
or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
The investigator should contact Galera Therapeutics, Inc. immediately if contacted by a 
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14.3. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
14.4. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Galera Therapeutics, Inc. or its representatives.  All protocol modifications must 
be submitted to the IRB/IEC/REB in accordance with local requirements.  Approval must be 
obtained before changes can be implemented. 
14.5. 
Information Disclosure 
14.5.1. 
Ownership 
All information provided by Galera Therapeutics, Inc. or its representatives, and all data and 
information generated by the site as part of the study (other than a subject’s medical records), are 
the sole property of Galera Therapeutics, Inc. 
14.5.2. 
Confidentiality 
All information provided by Galera Therapeutics, Inc. or its representatives, and all data and 
information generated by the site as part of the study (other than a subject’s medical records) will 
be kept confidential by the investigator and other site staff.  Information related to this study is 
subject to the confidentiality provisions of the Clinical Research Agreement between the 
investigative site and Galera Therapeutics, Inc. 
14.5.3. 
Publication 
All publication or presentation rights for the findings of the clinical investigation under this 
protocol shall be governed by the appropriate terms of the Clinical Research Agreement between 
the investigational site and Galera Therapeutics, Inc. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be monitored and managed in accordance with ICH GCP E6. 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Galera Therapeutics, Inc. or its representatives may conduct a quality assurance audit.  
Regulatory agencies may also conduct a regulatory inspection of this study.  Such 
audits/inspections can occur at any time during or after completion of the study.  If an audit or 
inspection occurs, the investigator and institution agree to allow the auditor/inspector direct 
access to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 


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16. 
ETHICS 
16.1. 
Ethical Conduct of the Study 
The investigator will ensure that this study is conducted in full compliance with the principles of 
the “Declaration of Helsinki” (version October 2008), International Conference on 
Harmonisation (ICH) guidelines, in particular ICH GCP E6, or with the laws and regulations of 
the country in which the research is conducted, whichever affords the greatest protection to the 
study patient. The investigator will also assure that the basic principles outlined in “ICH 
Guideline for Good Clinical Practice” as published in the Federal Register May 9, 1997, and all 
applicable Federal regulations including 21 CFR parts 50, 54, 56 and 312 are adhered to. 
16.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted, by the investigator, to an IRB/IEC/REB.  Approval from the 
IRB/IEC/REB must be obtained and a copy must be provided to Galera Therapeutics, Inc. or its 
representatives before initiating the conduct of any study procedures including screening or 
enrolling any patients into the trial. 
No modifications or deviations from this protocol other than those that are deemed medically 
necessary by the Principal Investigator or designated sub-investigator are to be made without 
prior, written approval by Galera Therapeutics, Inc.  Significant protocol deviations will be 
reported to Galera Therapeutics, Inc. and to the IRB/IEC/REB in accordance with its reporting 
policy. 
Any modifications made to the protocol by the sponsor after receipt of IRB/IEC/REB approval 
must be submitted to the committee for approval prior to implementation. 
16.3. 
Written Informed Consent 
In accordance with regulatory and local IRB/IEC/REB requirements, before study procedures are 
performed, patients will be informed about the study and required to sign the IRB/IEC/REB 
approved ICF. This form will be signed after adequate explanation of the aims, methods, 
objective and potential hazards of the study and prior to undertaking any study-related 
procedures. The Sponsor or its designee will provide an ICF template to the investigator. The 
Sponsor or its designee must approve changes to the ICF template prior to submission to the 
IRB/IEC/REB. Informed consent will be obtained according to the applicable IRB/IEC/REB 
requirements. No patient is to be screened or treated until an ICF, written in a language in which 
the patient is fluent, has been obtained. The signed ICF will be retained with the study records. 
Each patient will also be given a copy of his/her signed ICF.    
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Case Report Forms 
All required study data must be recorded on the electronic CRF provided by Galera 
Therapeutics, Inc. or its representatives.  The data recorded onto the electronic CRF is derived 
from the source documents.  The investigator shall ensure that all data in the electronic CRF is 
accurate and consistent with the source documents or that any discrepancies of the electronic 
CRF with source documents are explained (ICH E6 4.9.2).   
Electronic case report forms will be accessed by the study center for collection of all study data, 
and a copy of the electronic CRF will be provided to the site for the investigator files.  For each 
patient who receives study drug, the electronic CRF must be completed by site staff and must be 
signed electronically by the principal investigator in a timely fashion after data collection.  If a 
patient withdraws from the study, the electronic CRFs should be promptly completed and the 
reason for withdrawal must be noted.  If a patient is withdrawn from the study because of a drug-
related toxicity, thorough efforts should be made to clearly document the outcome. 
17.2. 
Retention/Inspection of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. 
Records of drug receipt and disposition, electronic file of CRFs, source documents, reports of 
this investigation and other study documentation must be maintained by the investigator for a 
period of at least two years following the date on which the investigational drug is approved by 
FDA or other applicable regulatory agency for marketing for the purposes that were the subject 
of the clinical investigations.  If no application is to be filed, records must be retained until two 
years following the date that the study is discontinued and the FDA or other applicable 
regulatory agency is notified.  If the application is not approved by the FDA or other applicable 
regulatory agency for such indication, records must be retained for two years after notification by 
Galera Therapeutics, Inc. of the FDA or other applicable regulatory agency decision.  The 
records must be available for copying and inspection if requested by regulatory authorities.   
Galera Therapeutics, Inc. should be notified in writing at least 30 days prior to the disposal or 
transfer to another location or party of any study records related to this protocol. 
 
 


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18. 
LIST OF REFERENCES 
1. Sonis ST. The impact, biology and therapeutic opportunities of oral mucositis. Oral 
Oncol 2009; 45:1015-20. 
2. Sonis ST, Elting LS, Keefe D, et al.  Perspectives on cancer therapy-induced mucosal 
injury: pathogenesis, measurement, epidemiology, and consequences for patients.  Cancer 
2004; 100 (9 Suppl):1995-2025. 
3. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT plus weekly 
cisplatin for advanced head and neck cancer: The University of Wisconsin experience.  
Head and Neck 2010; 32:599-606. 
4. Mendenhall WM, Amdur, RJ, and Palta JR.  Intensity-modulated radiotherapy in the 
standard management of head and neck cancer: promises and pitfalls. J Clin Oncol 2006; 
24:2618-23. 
5. Salama JK, Seiwert TY, Vokes EE.  Chemoradiotherapy for locally advanced head and 
neck cancer.  J Clin Oncol 2007; 25:4118-26.  
6. Nguyen-Tan PF, Zhang Q, Ang KK, et al.  Randomized Phase III Trial to Test 
Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for 
Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-
Term Report of Efficacy and Toxicity. J Clin Oncol 2014; 32:1-11. 
7. Ang KK, Zhang Q-E, Rosenthal DI, et al. Randomized Phase III Trial of Concurrent 
Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV 
Head and Neck Carcinoma: RTOG 0522. J Clin Oncol 2014; 32:2940-2950. 
8. Bonner JA, Harari PM, Giralt J, et.al.  Radiotherapy plus Cetuximab for Squamous Cell 
Carcinoma of the Head and Neck.  N Engl J Med 2006;354:567-78. 
9. Le Q-T, Kim HE, Schneider CJ, et.al.  Palifermin Reduces Severe Mucositis in Definitive 
Chemoradiotherapy of Locally Advanced Head and Neck Cancer: A Randomized, 
Placebo-Controlled Study.  J Clin Oncol 2011; 29:2808-2814. 
10. Henke M, Alfonsi M, Foa P, et.al.  Palifermin Decreases Severe Oral Mucositis of 
Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A 
Randomized, Placebo-Controlled Trial.  J Clin Oncol 2011; 29:2815-2820. 
11. Sonis ST.  Oral mucositis.  Anti-cancer drugs 2011; 22:607-12 
12. Elting LS, Cooksley CD, Chambers MS, et al. Risk outcomes, and costs of radiation-
induced oral mucositis among patients with head and neck malignancies.  Int J Radiat 
Oncol Biol Phys 2007; 68:1110-20. 
13. Bodey GP, Rodriguez V, Chang HY, et al. Fever and infection in leukemic patients: a 
study of 464 consecutive patients.  Cancer 1978; 41:1610-22. 
14. Elting LS, Keefe DM, Sonis ST, et al. Patient-reported measurements of oral mucositis in 
head and neck cancer patients treated with radiotherapy with or without chemotherapy: 
demonstration of increased frequency, severity, resistance to palliation, and impact on 
quality of life.  Cancer 2008; 113:2704-13. 


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15. Vera-Llonch M , Oster G, Hagiwara M, et al. Oral mucositis in patients undergoing 
radiation treatment for head and neck carcinoma.  Cancer 2006; 106:329-36. 
16. Russo G, Haddad R, Posner M, et.al.  Radiation treatment breaks and ulcerative mucositis 
in head and neck cancer.  Oncologist 2008;13:886-898. 
17. Ruescher TJ, Sodeifi A, Scrivani SA, et al. The impact of mucositis on alpha-hemolytic 
streptococcal infection in patients undergoing autologous bone marrow transplantation 
for hematologic malignancies. Cancer 1998; 82:2275-81. 
18. Nonzee NJ, Dandade NA, Patel U, et al.  Evaluating the supportive care costs of severe 
radiochemotherapy-induced mucositis and pharyngitis: results from a Northwestern 
University Cost of Cancer Program pilot study with head and neck and nonsmall cell lung 
cancer patients who received care at a county hospital, a Veteran’s Administration 
hospital, or a comprehensive cancer center. Cancer 2008; 113:1446-52. 
19. Keefe DM. Mucositis Guidelines: What have they achieved, and where to go from here?  
Support Cancer Care 2006;14:489-91. 
20. Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO Clinical Practice Guidelines for the 
Management of Mucositis Secondary to Cancer Therapy. Cancer 2014;120:1453-1461.  
21. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive 
therapy for hematologic cancers.  New Engl J Med 2004; 351:2590-8. 
22. MuGard prescribing information. 
23. Caphosol prescribing information. 
24. Rao NG, Trotti A, Kim J, et.al.  Phase II multicenter trial of Caphosol for the reduction of 
mucositis in patients receiving radiation therapy for head and neck cancer.  Oral 
Oncology 2014; 50:765-769. 
25. McCord J, Fridovich I.  Superoxide dismutase.  An enzymic function for erythrocuprein 
(hemocuprein). J Biol Chem 1969; 244:6049-55. 
26. Riley, PA.  Free radicals in biology: oxidative stress and the effects of ionizing radiation. 
Int J Radiat Biol. 1994: 65(1): 27-33. 
27. Buettner GR, Ng CF, Wang M, et.al.  A new paradigm:  Manganese superoxide 
dismutase influences the production of H2O2 in cells and thereby their biological state.  
Free Radic Biol Med 2006; 41(8): 1338-50. 
28. Sonis ST, Haddad R, Posner M, et al. Gene expression changes in peripheral blood cells 
provide insight into the biological mechanisms associated with regimen-related toxicities 
in patients treated for head and neck cancers.  Oral Oncol 2007;43:289-300. 
29. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004; 4:277-84. 
30. Lalla RV, Peterson DE. Treatment of mucositis, including new medications.  Cancer 
Journal 2006; 12(5): 348-54. 
31. Hahn T, Zhelnova E, Sucheston L, et al. A deletion polymorphism in glutathione-S-
transferase mu (GSTm1) and/or theta (GSTT1) is associated with an increased risk of 


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toxicity after autologous blood and marrow transplantation. Biol Blood Marrow 
Transplant 2010; 16:801-8. 
32. Epperly MW, Defilippi S, Sikora C, et al. Intratracheal injection of manganese 
superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not 
orthotopic tumors from irradiation. Gene Therapy 2000; 7:1011– 1018. 
33. Guo H, Seixas-Silver JA Jr, Epperly MW, et al. Prevention of radiation-induced oral 
cavity mucositis by plasmid/liposome delivery of the human manganese superoxide 
dismutase (SOD2) transgene. Radiat Res 2003;159:361-70. 
34. Delanian S, Baillet F, Huart J, et.al. Successful treatment of radiation-induced fibrosis 
using liposomal Cu/Zn superoxide dismutase: clinical trial. 1994. Radiotherapy and 
Oncology 1994; 32: 12-20. 
35. Thompson JS, Chu Y, Glass J, et.al.  The manganese superoxide dismutase mimetic, 
M40403, protects adult mice from lethal total body irradiation.  Free Radic Res 2010; 
44:529-40. 
36. Murphy CK, Fey EG, Watkins BA, et al. Efficacy of superoxide dismutase mimetic 
M40403 in attenuating radiation-induced oral mucositis in hamsters. Clin Cancer Res 
2008; 14:4292-7. 
37. Sonis S.  A Comparison of GC4419 and GC4403 for the Prevention of Oral Mucositis 
Induced by Acute Radiation in Hamsters. Biomodels Report Gal-03. Galera Report # 
1009-4419-0311. 
38. A Double-Blind, Placebo-Controlled, Single Rising Dose Study to Evaluate the Safety 
and Tolerability and Determine the Pharmacokinetics of M40419 Administered as a 15 
Minute Intravenous Infusion in Healthy Subjects, Galera clinical study report number 
U20-03-06-001. 
39. Sonis S. An Evaluation of GC4419 for the Prevention of Oral Mucositis Induced by 
Fractionated Radiation in Hamsters. Biomodels Report Gal-04. Galera Report # 1010-
4419-0311 
40. Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and 
neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. 
Radiother Oncology. 92(1) : 4–14.  
41. http://clinicaltrials.gov/ct2/show/NCT01302834?term=RTOG+1016&rank=1 , accessed 
12/2/14. 
42. Overgaard J, Hansen HS, Specht L, et.al.  Five compared with six fractions per week of 
conventional radiotherapy of squamous-cell carcinoma of head and neck:  DAHANCA 
6&7 randomised controlled trial.  Lancet 2003; 362: 933–40. 
43. Palifermin (Kepivance) prescribing information. 
44. Stiff PJ, Erder H, Bensinger WI, et.al.  Reliability and validity of a patient self-
administered daily questionnaire to assess impact of oral mucositis (OM) on pain and 


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daily functioning in patients undergoing autologous hematopoietic stem cell 
transplantation (HSCT).  Bone Marrow Transplantation 2006; 37: 393–401. 
45. Ang KK, Harris J, Wheeler R, et.al.  Human Papillomavirus and Survival of Patients with 
Oropharyngeal Cancer. N Engl J Med 2010;363:24-35. 
46. Fakhry C, Zhang Q, Nguyen-Tan PF, et.al.  Human Papillomavirus and Overall Survival 
After Progression of Oropharyngeal Squamous Cell Carcinoma.  J Clin Oncol 2014; 
32:3365-3373. 
47. Uno H, Claggett B, Tian L, et.al.  Moving Beyond the Hazard Ratio in Quantifying the 
Between-Group Difference in Survival Analysis. J Clin Oncol 2014; 32:2380-2385. 


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19. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Assessments 
Screening 
Phase 
Active Phase 
Post-Active Phase 
Within 28 
days  
of IMRT 
start 
Baseline 
IMRT 
Day 1 
Wk 1 
Days 
2 – 7 
Wk 2 
Days 
8 - 14 
Wk 3 
Days 
15 - 21 
Wk 4 
Days 
22 - 28 
Wk 5 
Days 
29 - 35 
Wk 6 
Days 
36 - 42 
Wk 7 
Days 
43 - 49 
Last Day 
of IMRT 
or Early 
Term1 
Post-IMRT 
Wks 1 
through 8 
(±2 D)2 
Months 3, 
12, & 24 
Post-IMRT  
(±30 D) 
Months 
6, 9, 16 & 20 
Post-IMRT  
(±30 D) 
Informed consent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and HNC histories4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete PE5 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed PE 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Dental exam/IMRT clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, ECOG, weight6 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
Record BSA7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging9 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Tumor Assessment10 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Concomitant medications11 
X 
X 
Weekdays 
X 
X 
 
 
Adverse Events12 
 
X 
Weekdays 
X 
X 
 
 
ECG (12-lead)13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
OM assessment14 
X 
X 
X 
Twice-weekly 
X 
X 
X 
 
 
Trismus assessment15 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Xerostomia assessment16 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
OMDQ, analgesic recording17 
 
X 
Daily including weekends 
X 
X 
 
 
Gastrostomy tube placement/use 
 
X 
X 
Twice-weekly 
X 
X 
 
 
 
Unscheduled office visits, ER visits, or 
hospitalizations 
 
 
 
Twice-weekly 
X 
X 
 
 
 
Placement of indwelling venous catheters  
X 
 
 
 
Blood draw: Lab safety tests18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
 
 
 
Blood draw: PK samples20 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Blood draw: Cytokines21 
X 
X 
 
OM Visit 2 
 
OM Visit 2 
 
OM Visit 2 
 
X 
 
 
 
Blood draw: RNA22 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Dosing GC441923 
 
X 
Days 
2-5 
Days 
8-12 
Days 
15-19 
Days 
22-26 
Days 
29-33 
Days 
36-40 
Days 
43-47 
 
 
 
 
 


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1 If a patient ends study participation early and withdraws consent, all last day of IMRT procedures should be completed. 
2 The Post-IMRT Weeks 1 through 8 Follow-up Visits will be scheduled based on the last day of IMRT. Patients will be seen weekly (every 7 ± 2 calendar days) 
until WHO < 2. 
3 See protocol Sections 7.1 and 7.2. 
4 The HNC history should include tumor HPV status, staging (AJCC) information, prior treatments, and confirmation of histopathological diagnosis of SCC. 
Medical conditions and illnesses that have occurred since the patient signed the ICF up until the date of randomization should be recorded as medical history. 
Medical history also includes tobacco and alcohol use history. 
5 At the Screening and Last Day of IMRT Visits, a complete physical examination will be conducted. 
6 Vital signs (temperature, systolic and diastolic blood pressures, heart rate, and respiration rate), body weight, and ECOG will be obtained and recorded at the 
Screening and Baseline Visits, once during Weeks 4 and 7, and at the Last Day of IMRT Visit. All vital signs should be measured following 2 minutes of rest 
in the sitting position. 
7 For patients receiving tri-weekly cisplatin, body surface area (BSA) will be recorded to confirm cisplatin dosing at the Baseline Visit and once during Weeks 4 
and 7. For patients receiving weekly cisplatin, body surface area (BSA) will be recorded to confirm cisplatin dosing at the Baseline Visit and once per week 
until chemotherapy is completed. 
8 For a woman of childbearing potential, serum pregnancy test must be performed at the Screening Visit.  
9 Radiographic imaging must be performed within 60 days prior to the first day of IMRT and at Months 12 and 24 Post-IMRT for all patients. Patients treated 
definitively (as opposed to post-operatively) will also undergo imaging at Month 3 Post-IMRT to assess tumor response/clearance to the degree possible. 
Radiographic imaging is highly recommended at any Post-IMRT follow-up visit at which disease progression is suspected by the treating physician. If 
radiographic imaging is performed, both local/regional recurrence and distant metastases should be evaluated.   
10 At the Last Day of IMRT Visit, a clinical tumor assessment will be conducted. A neck and oral exam is sufficient at the Last Day of IMRT Visit if disease 
progression is not suspected. If disease progression is suspected, a laryngopharyngoscopy should be conducted. At Months 3, 6, 9, 12, 16, 20, and 24, a 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required if disease progression is suspected to evaluate local/regional or distant 
progression. 
11 All concomitant therapies (e.g., prescription and over-the-counter medications) taken by patients on or after the date of randomization through 30 days 
following the last GC4419/placebo, IMRT or cisplatin (i.e. whichever occurs last) dose will be collected in the CRF, except for narcotics (narcotics will only be 
captured from the Baseline Visit through the Last Day of IMRT Visit).  Additionally, any concomitant therapies used to treat any serious or related adverse 
event will be recorded in the CRF.  
12 AEs and SAEs with onset dates on or after the date of randomization through 30 days following the last GC4419/placebo, IMRT or cisplatin (i.e. whichever 
occurs last) dose will be recorded on the CRF.  All patients with SAEs will be followed until the events resolve, stabilize, become chronic, the patient 
completes the study, or the patient is lost to follow-up. 
13 Ventricular rate and P-R, QRS, QT, and QTc intervals will be assessed and recorded. An ECG will be conducted at the Screening and Baseline Visits, during 
Week 4, and at the Last Day of IMRT Visit.  
14 All OM assessments must be performed by trained evaluators. The extent of the patient’s OM will be scored using the WHO OM toxicity scale. OM 
assessments will be completed at the Screening Visit, at the Baseline Visit, and twice weekly (no less than 48 hours apart) within each 5-day IMRT period. For 
Week 1, the first OM assessment will occur at the Baseline Visit; one additional OM assessment must occur at least 48 hours later during the week. The extent 
of the patient’s OM will be scored using the WHO OM toxicity scale. If a patient has ulcerative OM (WHO ≥ 2) at the Last Day of IMRT Visit, visits for OM 
will be repeated weekly (every 7 days ± 2 days) until the WHO score is 0 or 1 or the patient is 8 weeks post-IMRT, whichever occurs first. 
15 Using a Sponsor-provided ruler, the distance in millimeters between the incisal edges of the mandibular and maxillary incisors at midline will be measured to 
determine the maximum opening of the mouth that the patient can achieve at the Baseline Visit and Months 3, 6, 9, 12, 16, 20, and 24 Post-IMRT Visits.   
16To assess xerostomia, patients will complete a VAS instrument at the Baseline Visit and 3, 6, 9, 12, 16, 20, and 24 Month Post-IMRT Visits.  


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17 Beginning at the Baseline Visit (IMRT Day 1) and through the Last Day of IMRT Visit, patients will complete a daily diary (including weekends) containing 
the OMDQ and questions regarding narcotic use. If a patient returns for weekly visits following the last day of IMRT because WHO ≥ 2, the OMDQ only will 
be completed at the time of the weekly clinic visit.   
18 Clinical laboratory measurements will be conducted at the Screening Visit, twice during Week 1 (once at the Baseline Visit and again on Day 3, 4 or 5), and 
once weekly from Week 2 through the last day of IMRT. Clinical laboratory measurements at these visits will include the hematology profile (hemoglobin, 
hematocrit, red blood cell count, white blood cell count with differential, and platelet count.  Differential to include total neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) and chemistry profile (glucose, BUN, creatinine, sodium, potassium, calcium, albumin, total protein, total bilirubin, direct bilirubin, 
alkaline phosphatase, ALT (SGPT), AST (SGOT), chloride, phosphate, bicarbonate). 
19 If safety labs have already been drawn during the study week in which the last day of IMRT or early termination visit falls, then lab safety tests (chemistry and 
hematology profiles) do not need to be conducted on the last day of IMRT or at the early termination visit.  If safety labs have not been drawn during the 
current study week at the time of the early termination visit or on the last day of IMRT, then safety labs should be drawn on that day.  Safety labs only need to 
be drawn once per study week after Week 1. 
20Blood samples will be collected for GC4419 pharmacokinetic (PK) measurements at Baseline, Day 2, Day 22 and Day 23. See Table 10 for additional 
information.  
21For cytokine analysis, blood samples will be collected at the Screening Visit (within 28 days of IMRT start but at least 72 hours prior to Baseline), at the 
Baseline Visit, Week 2 OM Visit 2, Week 4 OM Visit 2, Week 6 OM Visit 2, and at the Last Day of IMRT Visit. Whenever possible, blood draws for cytokine 
analysis should be conducted at OM Visit 2 for each protocol-specified week; however, if blood draws must be taken on another day within a given week, it 
will not be considered a protocol deviation. 
22If the patient consents separately, blood samples will be collected at the Screening Visit (within 28 days of IMRT start but at least 72 hours prior to Baseline) 
and at the Last Day of IMRT Visit for the assessment of gene expression patterns prior to receiving the first dose of GC4419 and upon completion of GC4419 
doses.   
23GC4419 will be administered up to 35 times: weekly, Monday through Friday, beginning at Baseline (IMRT Day 1) and through Study Day 47 (end of IMRT). 
IMRT must begin no longer than 60 min following the end of the GC4419 infusion.  If IMRT is not received on any given day due to a treatment break or 
unforeseen circumstances, GC4419 should not be administered on that day.  Patients should resume GC4419 administration when IMRT resumes. 
 


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20. 
APPENDIX 2: WHO SCORE 
Grade 
Scoring Criteria 
Grade 0: 
None 
Grade 1: 
Erythema and Soreness; No ulcers 
Grade 2: 
Ulcers; Able to eat a solid diet 
Grade 3: 
Ulcers; Requires a liquid diet 
Grade 4: 
Ulcers; Not able to tolerate a solid or liquid diet; Requires IV or tube feeding 


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21. 
APPENDIX 3: ORAL MUCOSITIS DAILY QUESTIONNAIRE  
 


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22. 
APPENDIX 4: PERFORMANCE STATUS CONVERSION 
Performance Status Conversion: ECOG - Karnofsky  
ECOG 
Karnofsky 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all pre-
disease performances without 
restriction. 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease. 
1 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature, office work 
80 
Normal activity with effort, some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or do active work 
2 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities; Up and about more 
than 50% of waking hours 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs 
50 
Requires considerable assistance and frequent 
medical care 
3 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated; 
Death not imminent 
4 
Completely disabled; Cannot carry 
on any self-care; Totally confined to 
bed or chair 
20 
Very sick, hospital indicated, death not 
imminent 
10 
Moribund, fatal processes progressing rapidly 
5 
Death 
0 
Death 


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23. 
APPENDIX 5: NATIONAL CANCER INSTITUTE-COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS, 
VERSION 4 
See the following website link for the complete NCI-CTCAE Version 4: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40_conversion 
 
 


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24. 
APPENDIX 6: XEROSTOMIA ASSESSMENT (LEVEQUE, 1993) 
Instructions: For each question below, mark your answer by placing a vertical (up & down) 
line on the horizontal (left to right) scale. 
1. Rate the difficulty you experience in speaking due to dryness. 
 
 
Easy 
Very difficult 
2. Rate the difficulty you experience in swallowing due to dryness.  
 
 
 
Easy 
Very difficult 
3. Rate the dryness of your mouth.  
 
Not dry at all 
Very dry 
4. Rate the dryness of your throat.  
 
Not dry at all 
Very dry 
5. Rate the mouth and tongue discomfort you have due to dryness.  
 
Comfortable                                                            
Extremely uncomfortable 
 
  
 
 
 


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25. 
APPENDIX 7.  RECOMMENDED REGIMENS FOR HIGH-RISK 
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING 
(CINV) PER ASCO AND MASCC GUIDELINES 
Note:  Both ASCO and MASCC define single-agent IV cisplatin as a “high risk” regimen for 
CINV. 
 
ASCO: 
http://www.instituteforquality.org/sites/instituteforquality.org/files/antiemetic_dosing_clinical_to
ol_9_21_11_correction_may_2014.pdf, accessed 27 March 2015 
 
Drug Class 
Agent 
Dose on Day of Chemotherapy 
Dose(s) on 
Subsequent Days 
NK1 Antagonist 
Aprepitant 
125 mg oral 
80 mg oral; days 2 
and 3 
Fosaprepitant 
150 mg IV 
Day 1 only 
5-HT3 Receptor 
Antagonist 
Granisetron 
2 mg oral OR 1 mg or 0.01 mg/kg IV 
Day 1 only 
Ondansetron 
8 mg oral twice daily OR 8 mg or 0.15 
mg/kg IV 
Palonosetron 
0.50 mg oral OR 0.25 mg IV 
Dolaseetron 
100 mg oral ONLY 
Tropisetron 
5 mg oral OR IV 
Ramosetron 
0.3 mg IV 
Corticosteroind 
if aprepitant is 
used* 
Dexamethasone 
12 mg oral OR IV 
8 mg oral OR IV; 
days 2-3 OR days 2-
4* 
Corticosteroid if 
fosaprepitant is 
used* 
Dexamethasone 
12 mg oral OR IV 
8 mg oral OR IV day 
2; 8 mg oral OR IV 
twice daily on days 3-
4* 
*Presumes patients are receiving an NK1 antagonist.  If they are not, the dexamethasone dose should be 
adjusted to 20 mg on day 1 and 16 mg on days 2-4. 
 
Special Note Regarding the 2/Nov/15 Guideline Update: The oral combination of netupitant and 
palonosetron (NEPA) plus dexamethasone is an additional treatment option in this setting.  
(http://jco.ascopubs.org/content/early/2015/10/26/JCO.2015.64.3635.full) 
In the event that the 2015 Guidelines are updated, the new recommendations should be followed 
effective immediately upon issuance. 
MASCC:  http://www.mascc.org/assets/Guidelines-Tools/mascc_antiemetic_english_2014.pdf, 
accessed 26 March 2015 


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Guideline for the prevention of acute nausea and vomiting:  To prevent acute nausea and 
vomiting following chemotherapy of high emetic risk, a three-drug regimen including single 
doses of a 5-HT3 receptor antagonist, dexamethasone 12 mg, and aprepitant 125 mg (or 
fosaprepitant 150 mg) given before chemotherapy is recommended.  (Dosing of 5-HT-3 receptor 
antagonist and dexamethasone as per ASCO guidelines, except no recommendation made for 
ramositron.) 
Guideline for the prevention of delayed nausea and vomiting: In patients receiving cisplatin 
treated with a combination of aprepitant (or fosaprepitant*), a 5-HT3 receptor antagonist and 
dexamethasone to prevent acute nausea and vomiting, the combination of dexamethasone and 
aprepitant (80 mg orally per day for the 2 days following chemotherapy)* is suggested to prevent 
delayed emesis, on the basis of its superiority to dexamethasone alone.  
• *However, if fosaprepitant is used in Day 1, only dexamethasone is required at days 2 
- 4 post-chemotherapy 
Additional note:  NEPA (a fixed-dose combination of netupitant and palonosetron) has been 
approved by the FDA in October 2014 and may be considered. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol GT-201 
 
Galera Therapeutics, Inc. 
Confidential 
 
 
 
 
 
 
 
 
 
   Amendment 6 
 
105 
 
 
  
 
26. 
APPENDIX 8: SUMMARY OF CHANGES IN AMENDMENT 6 
The GT-201 Protocol Amendment 5, dated 8 May 2017, is replaced by this Protocol Amendment 
6, dated 19 October 2017. This Protocol Amendment 6 applies to all sites. 
Listed below are a summary of substantive changes incorporated into Amendment 6.  
Administrative changes, such as cross-linking and typographical/grammatical corrections have 
also been made, which may not be summarized.  A red-line version which identifies all non-
formatting changes (i.e., “was-is” document) is incorporated by reference to this document as, 
“GT-201: Redline Changes from Protocol Amendment 5 to Protocol Amendment 6” (Note: The 
page numbers in the final version may not match exactly the page numbers in the redline version 
due to the listing of previous and new text). 
1. Change: Change method of handling multiple comparisons from the prior Hochberg 
method to a fixed sequence analysis approach. As part of the change in multiple testing, 
add as secondary endpoints incidence of Grade 4 OM and onset of severe OM, expressed 
as number of IMRT fractions at onset. 
Rationale: In consultation with scientific, statistical, and regulatory advisors, the 
Sponsor has determined that a fixed sequential approach provides a more appropriate way 
to assess the effects of the two active doses of GC4419.  Note: this change is made prior 
to database lock or study unblinding, and is not informed by examination of the study 
data.   
2. Change: Specify that, in the event of discrepancies between the protocol and the 
Statistical Analysis Plan, the latter will control the evaluations conducted.  
Rationale: Clarification.  
3. Change: Change “28%” to “29%” in Table 5, which summarizes severe OM results from 
GT-001.  
Rationale: Correct a previous rounding error.  
4. Change:  Move incidence of Grade 4 OM and onset of Grade 3-4 OM from exploratory 
to secondary endpoints. 
Rationale: Consistency with the adoption of fixed sequential hypothesis testing, in which 
these endpoints are now included in the testing sequence.   
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Galera Therapeutics, Inc 
 
Protocol #: GT-201 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Trial of the 
Effects of Intravenous GC4419 on the Incidence and Duration of Severe Oral Mucositis 
(OM) in Patients Receiving Post-Operative or Definitive Therapy with Single-Agent 
Cisplatin plus IMRT for Locally Advanced, Non-Metastatic Squamous Cell Carcinoma of 
the Oral Cavity or Oropharynx 
 
Statistical Analysis Plan 
 
Version 2.0 
19-Oct-2017 
 
Prepared for: 
Jeff Brill 
Director Clinical Development 
 Galera Therapeutics, Inc. 
2 West Liberty Boulevard 
 Suite 110  
 Malvern, PA  19355 
 
Prepared by: 
 
Novella Clinical 
 
1700 Perimeter Park Dr. 
 
Morrisville, NC  27560 
 
 
 
 
 
 
 
 
 
 
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 2 of 47  
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BSA 
Body  Surface Area 
°C 
Degrees Centigrade 
CM 
Concomitant Medication 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTM 
Clinical Trial Material 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ER 
Emergency Room 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
Gy 
Gray 
HIPAA 
Health Insurance Portability and Accountability Act 
HNC 
Head and Neck Cancers 
HSCT 
Hematopoietic Stem Cell Transplantation 
HPV 
Human Papilloma Virus 
IMRT 
Intensity-Modulated Radiation Therapy 
ITT 
Intention to Treat 
IV 
Intravenous 
IXRS 
Interactive Response Technology 
kg 
Kilogram 
lb 
Pound 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger RNA 
NCI 
National Cancer Institute 
N/V 
Nausea/Vomiting 
OM 
Oral Mucositis 
OMDQ 
Oral Mucositis Daily Questionnaire 
PK 
Pharmacokinetic 
Q3 
Every 3 
OS 
Overall Survival 
PFS 
Progression Free Survival 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SOM 
Severe Oral Mucositis 
STD 
Standard Deviation 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 3 of 47  
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 4 of 47  
CONTENTS 
I.Introduction ............................................................................................................................ 6 
A. Background ............................................................................................................. 6 
B. Protocol and Amendment History .......................................................................... 7 
II.Protocol Objectives ............................................................................................................... 8 
A. Primary .................................................................................................................... 8 
B. Secondary ................................................................................................................ 8 
C. Exploratory ............................................................................................................. 9 
III.Study Endpoints ................................................................................................................. 10 
A. Primary .................................................................................................................. 10 
B. Secondary .............................................................................................................. 10 
C. Exploratory ........................................................................................................... 11 
IV.Study Design ...................................................................................................................... 13 
A. Design Overview .................................................................................................. 13 
B. Study Population ................................................................................................... 13 
C. Sample Size ........................................................................................................... 14 
D. Treatment Randomization ..................................................................................... 14 
E. Assessment Schedule ............................................................................................ 15 
V.Interventions........................................................................................................................ 15 
A. Clinical Trial Material........................................................................................... 15 
B. Study Procedures .................................................................................................. 15 
VI.General Analytical Considerations .................................................................................... 16 
A. Data Sources ......................................................................................................... 16 
B. Definition of Baseline ........................................................................................... 16 
C. Missing Data ......................................................................................................... 17 
D. Multiple Study Centers ......................................................................................... 17 
E. Covariate Adjustment ........................................................................................... 17 
F. Interim Analyses or Timing of Analyses .............................................................. 18 
G. Test Sizes .............................................................................................................. 19 
H. Multiple Comparisons ........................................................................................... 19 
I. Analysis Populations ............................................................................................. 20 
J. Data Display Characteristics ................................................................................. 21 
K. Blinded Review of Data ........................................................................................ 22 
L. Balance of Treatment Assignments ...................................................................... 22 
VII.Subject Accountability ..................................................................................................... 22 
A. Subject Characteristics .......................................................................................... 23 
B. Disposition ............................................................................................................ 24 
C. Protocol Deviations and Population Inclusions .................................................... 25 
VIII.Efficacy Analyses ........................................................................................................... 25 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
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A. Efficacy Outcomes ................................................................................................ 25 
B. Primary Efficacy Outcome Analysis .................................................................... 29 
C. Secondary Efficacy Outcome Analysis ................................................................ 30 
D. Exploratory Efficacy Analyses ............................................................................. 30 
E. Other Efficacy-Related Summaries ...................................................................... 31 
IX.Analyses of Tumor Endpoints ........................................................................................... 32 
A. Tumor Outcomes .................................................................................................. 32 
B. Analysis of Tumor Outcomes ............................................................................... 32 
X.Safety Analyses ................................................................................................................... 33 
A. Exposure ............................................................................................................... 33 
B. Adverse Events ..................................................................................................... 35 
C. Nausea and Vomiting Adverse Events ................................................................. 37 
D. Xerostomia and Trismus ....................................................................................... 38 
E. Clinical Laboratory Results .................................................................................. 38 
F. Vital Signs ............................................................................................................. 38 
G. Concomitant Medications ..................................................................................... 38 
H. Electrocardiogram (ECG) ..................................................................................... 39 
I. ECOG Performance Status ................................................................................... 39 
XI.Analysis of Patient Reported Outcomes ............................................................................ 39 
XII.Analysis of Health and Economic Outcomes ................................................................... 39 
XIII.Biomarker Analyses ........................................................................................................ 40 
XIV.References ....................................................................................................................... 41 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ................................................................ 42 
APPENDIX 2: HYPOTHETICAL EXAMPLES FOR IMPUTING MEDIAN DURATION 
AMONG SUBJECTS WITH UNKNOWN SEVERE OM RESOLUTION .......................... 45 
APPENDIX 3: HYPOTHETICAL EXAMPLES FOR IMPUTING MEDIAN DURATION 
AMONG SUBJECTS WITHOUT SEVERE OM BEFORE LOSS TO FOLLOW ............... 47 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 6 of 47  
I. 
Introduction 
 
A. Background 
 
Oral mucositis (OM) is a common, problematic, and painful complication of 
cancer therapy in regimens that include radiation to the head and neck1. A 
majority of patients receiving combined chemoradiotherapy for head and neck 
cancer (HNC) can be expected to develop severe OM2, and nearly all HNC 
patients receiving radiation therapy with concurrent cisplatin are expected to 
develop ulcerative OM3.  
 
OM is characterized by mouth sores that typically progress to an ulcerative state 
after two or three weeks of radiotherapy, or a cumulative dose of 20-30 Gy. 
These sores make eating and swallowing difficult, and can induce weight loss 
and dehydration. In addition to interrupting food intake, OM has a substantial 
number of comorbidities, including reduced performance status, secondary 
infections at the sites of the ulcers, diminished quality of life outcomes, 
xerostomia, taste change, and trismus. In addition, OM can precipitate other 
serious medical complications that require frequent hospitalizations and breaks in 
treatment, which can compromise the anti-tumor efficacy of the therapy 
administered to treat the cancer.  
 
In addition to several interventions that are recommended to prevent OM, 
palifermin is the only FDA-approved drug intervention therapy. Its use, however, 
is limited to a very small cohort of patients, those who are receiving autologous 
hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. 
The Investigational Product of the current study, GC4419, is a compound that 
can potentially be used in a larger number of eligible patients. It has been shown 
in an earlier Phase 1b/2a trial to reduce the incidence and severity of OM in 
patients receiving IMRT combined with cisplatin for the treatment of squamous 
cell carcinoma of the oral cavity or oropharynx. The current study will examine 
GC4419 efficacy further in a three-arm, randomized (1:1:1) placebo-controlled 
Phase 2 trial in patients with locally advanced, non-metastatic squamous cell 
HNC of the oral cavity or oropharynx. Two doses of GC4419, one “low” and one 
“high,” will be evaluated against placebo in patients receiving a backbone 
regimen of cisplatin plus IMRT. The primary objective is to evaluate and 
compare the duration of severe OM between each of the two GC4419 treatment 
groups and the placebo group. 
 
The protocol for Study GT-201 describes the general approach to analysis of data 
from the study.  This analysis plan describes additional detail needed to complete 
such an analysis. 
 
 
  


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
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B. Protocol and Amendment History 
   
This Statistical Analysis Plan (SAP) is based on GT-201 Protocol Amendment 5.  
See below for a list of all protocol versions. 
 
Version 
Approval Date 
Salient Changes, if any* 
Original Protocol 
20 April 2015 
 
Amendment 1 
16 November 2015 
Removal of Interim Analysis; 
Change in primary objective; 
Addition of exploratory endpoint; 
Change to reporting period for 
adverse events; Update to antiemetic 
guidelines. 
Amendment 2 
22 July 2016 
Extension to Canada; Addition of 
Bezydamine to list of prohibited 
medications 
Amendment 3 
26 October 2016 
Extension of tumor, xerostomia, and 
trismus follow-up from one to two 
years post-IMRT; Addition of 
Caphosol to list of prohibited 
medications 
Amendment 4 
21 December 2016 
Addition of exclusion criterion #16; 
Addition of Pyridostigmine and 
other drugs that could create a risk 
of increased carotid sinus sensitivity, 
symptomatic bradycardia, or 
syncopal episodes to list of 
prohibited medications; 
Modification of dose reduction 
criteria 
Amendment 5 
08 May 2017 
Increase in sample size; 
Demotion of secondary endpoints; 
Addition of exploratory endpoints 
Amendment 6 
20 October 2017 
Change in multiplicity adjustment 
for Type I error from Hochberg 
correction to sequential testing of 
hypotheses 
 
Promotion of incidence of Grade 4 
OM through completion of IMRT 
and onset of severe OM as 
secondary endpoints. 
* Changes expected to require accommodation in analysis plan. 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 8 of 47  
 
This SAP will govern the analysis of data from this study.  The plan may be 
modified until the time of treatment unblinding.  Any deviations from the 
analysis plan, including any after the time of treatment unblinding, will be 
documented as such in the study report.   
 
 
 
II. 
Protocol Objectives 
 
A. Primary 
 
The protocol lists the following primary objective:   
 
 
To evaluate and compare the duration of severe OM, as assessed from the 
first determination of ≥ Grade 3 OM to the first instance of non-severe OM 
(≤ Grade 2), without a subsequent instance of ≥ Grade 3. 
 
B. Secondary 
 
The protocol lists the following secondary objectives: 
 
 Efficacy 
 
o To evaluate and compare the effects of GC4419, administered at each of 
two daily doses vs. placebo, on the cumulative incidence of severe OM, 
defined as any occurrence of WHO Grade 3-4 OM, from the first IMRT 
fraction through the delivery of the 30th IMRT fraction (approximately 
60 Gy delivered to tumor)  
 
o To evaluate and compare the cumulative incidence of severe OM from 
the first IMRT fraction through the last IMRT fraction  
 
o To evaluate and compare the cumulative incidence of Grade 4 OM from 
the first IMRT fraction through the last IMRT fraction  
 
o To evaluate and compare the time to onset of severe OM expressed as the 
number of IMRT fractions delivered at onset of severe OM 
 
 Safety 
 
o To evaluate and compare the safety of GC4419 at the treatment 
assignment of each respective arm  
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
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o To evaluate and compare the effect of treatment assignment on tumor 
outcomes (locoregional failure, distant metastases, progression-free 
survival, overall survival)  
 
C. Exploratory 
 
The protocol lists the following exploratory objectives: 
 
 To evaluate and compare duration of severe OM among subjects with severe 
OM 
 
 To evaluate and compare the time to onset of severe OM: expressed both as 
cumulative IMRT dosage delivered and as time (days) at onset of severe OM  
 
 To evaluate and compare the time to onset of severe OM among subjects 
with severe OM: time (days), cumulative IMRT dosage, and number of 
IMRT fractions delivered at onset of severe OM  
 
 To evaluate and compare the duration of severe OM, as assessed by the 
number of instances of severe OM of ≥ 7 days’ duration, defined as severe 
OM recorded at two or more consecutive OM evaluations  
 
 To evaluate and compare severe OM incidence from the first IMRT fraction 
through the end of post-IMRT early follow-up; post-IMRT early follow-up 
will extend for up to eight weeks post the last IMRT fraction administered or 
until a given patient’s OM is WHO Grade 0 or 1  
 
 To evaluate and compare cumulative severe OM incidence at cumulative 
delivery of 20-29, 30-39, 40-49, or 50-59 Gy of IMRT 
  
 To evaluate and compare the duration of Grade 4 OM from the first IMRT 
fraction through the last IMRT fraction  
 
 To evaluate and compare the areas under the OM-severity vs. cumulative 
IMRT dosage curves  
 
 To evaluate and compare the number and percentage of patients with severe 
OM on more than one visit prior to Week 6, Visit 2  
 
 To evaluate and compare the total number of days (per patient) of severe OM 
through the end of IMRT  
 
 To evaluate and compare the effects of GC4419 on the incidence, onset, and 
duration of ulcerative (≥ Grade 2) OM  
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
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 To evaluate and compare treatment delivery and delays (number and duration 
of delays) of IMRT and cisplatin, to include cisplatin dose reductions.  
 
 To evaluate and compare the effects of GC4419 on other specific toxicities of 
interest associated with concurrent chemoradiation: xerostomia, trismus, 
fatigue, weight loss, radiation dermatitis, and dysgeusia (changes in taste)  
 
 To evaluate and compare the effects of treatment on patient-reported 
outcomes as obtained using the Oral Mucositis Daily Questionnaire (OMDQ)  
 
 To evaluate and compare the use of narcotic analgesics by patients according 
to treatment assignment  
 
 To evaluate and compare frequency, use, and reasons for use of gastrostomy 
tubes  
 
 To evaluate and compare the use and complications of indwelling venous 
access devices  
 
 To evaluate and compare the frequency and reasons for unscheduled 
hospitalizations  
 
 To assess the effects of treatment assignment on circulating cytokine levels 
and gene expression levels  
 
 
III. 
Study Endpoints 
 
A. Primary 
 
The primary endpoint is the duration of severe OM, which is defined as the 
number of days from the first occurrence of WHO Grade 3 or 4 OM through the 
first occurrence of non-severe (≤ Grade 2) without a subsequent instance of ≥ 
Grade 3 OM. Subjects with complete study follow-up for severe OM as 
described in the protocol and who do not develop severe OM will be considered 
to have durations of 0 days. 
 
B. Secondary 
 
The protocol describes as secondary endpoints the following: 
 
 Cumulative incidence of severe OM, defined as any occurrence of WHO 
Grade 3-4 OM, from the first IMRT fraction through the delivery of the 30th 
IMRT fraction  


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
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 Evaluate and compare the safety of GC4419 at the treatment assignments of 
each respective arm 
 Cumulative incidence of severe OM from the first IMRT fraction through the 
last IMRT fraction  
 Effect of treatment assignment on tumor outcomes (locoregional failure, 
distant metastases, progression-free survival, overall survival)  
 
 Cumulative incidence of Grade 4 OM from the first IMRT fraction through 
the last IMRT fraction 
 
 Onset of severe OM, expressed in number of IMRT fractions delivered at 
onset of severe OM 
 
C. Exploratory 
 
The protocol describes the following exploratory endpoints:  
 
 Duration of severe OM, excluding those without severe OM (i.e., durations 
of 0 days) 
 Onset of severe OM, expressed both in cumulative IMRT dosage and  time 
(days) at onset of severe OM  
 Onset of severe OM, expressed as cumulative IMRT dosage, time (days), and 
number of IMRT fractions delivered at onset of severe OM, when excluding 
those without severe OM (i.e., durations of 0 days) 
 Number of instances of severe OM lasting ≥ 7 days, defined as two or more 
consecutive observations of severe OM  
 Cumulative incidence of severe OM from the first IMRT fraction through the 
end of post-IMRT early follow-up; post-IMRT early follow-up will extend 
for up to eight weeks post the last IMRT fraction administered or until a 
given patient’s OM is WHO Grade 0 or 1  
 
 Cumulative severe OM incidence at cumulative delivery of 20-29, 30-39, 40-
49, or 50-59 Gy of IMRT  
 
 Duration of Grade 4 OM from the first IMRT fraction through the last IMRT 
fraction 
 
 Areas under the OM-severity vs. cumulative IMRT dosage curves  
 
 Number and percentage of patients with severe OM on more than one visit 
prior to Week 6, Visit 2  
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 12 of 47  
 Total number of days (per patient) of severe OM though the end of IMRT  
 
 Incidence, onset, and duration of ulcerative (≥ Grade 2) OM  
 
 Number and duration of delays of IMRT and cisplatin, or of cisplatin dose 
reductions  
 
 Other specific toxicities of interest associated with concurrent 
chemoradiation:  
 
o Xerostomia (assessed using a five-point Visual Analog Scale of Leveque)  
 
o Trismus, based on measurement of jaw opening  
 
o Fatigue 
 
o Weight loss, from serial patient weights in scheduled study visits  
 
o Radiation dermatitis per NCI-CTCAE v4.03  
 
o Dysgeusia (changes in taste) per NCI-CTCAE v4.03  
 
 Scores in individual questions from the Oral Mucositis Daily Questionnaire 
(OMDQ)  
 
 Use of narcotic analgesics by patients according to treatment assignment  
 
o Percentage of patients using opioid narcotics  
 
o Time and cumulative IMRT delivered to first opioid narcotic use  
 
o Median total opioid narcotic dose (morphine equivalents) with 25th-75th 
percentiles  
 
 Frequency, use, and reasons for use of gastrostomy tubes  
 
 Frequency, use and complications of indwelling venous access devices  
 
 Frequency and reasons for unscheduled hospitalizations  
 
 Levels of selected circulating cytokines (cytokine selection informed by 
proposed GC4419 mechanism of action and Phase 1 results)  
 
 To assess the effects of treatment assignment on circulating cytokine levels 
and gene expression levels.  
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 13 of 47  
 
IV. 
Study Design 
 
A. Design Overview  
 
Study GT-201 is a Phase 2, randomized, double-blind, placebo-controlled, multi-
center study conducted in the US and Canada to evaluate Galera’s GC4419 
administered via IV for the prevention of radiation induced oral mucositis in 
patients receiving chemotherapy and radiation for SCCHN, limited to the oral 
cavity or oropharynx.  Approximately 216 subjects who meet eligibility criteria 
and consent to participate in the study are randomly assigned equally to one of 
the following treatment groups. Randomization will be stratified according to 
HPV status at baseline (positive vs. negative) and initial chemotherapy schedule 
(once every 3 weeks vs. once a week cisplatin). 
 Arm A: 30 mg GC4419 per day + IMRT 2.0-2.2 Gy per day + Cisplatin 
(80-100 mg/m2 every 3weeks or 30-40 mg/m2 once weekly)  
 Arm B: 90 mg GC4419 per day + IMRT 2.0-2.2 Gy per day + Cisplatin 
(80-100 mg/m2 every 3weeks or 30-40 mg/m2 once weekly) 
 Arm C: Placebo daily + IMRT 2.0-2.2 Gy per day + Cisplatin (80-100 
mg/m2 every 3weeks or 30-40 mg/m2 once weekly) 
 
After completion of screening assessments and determination of eligibility, 
enrolled patients will be randomized into one of the above treatment arms. Each 
subject will receive blinded study treatment (GC4419 or placebo) via a 
60-minute IV infusion, followed within 60 minutes by a 2.0-2.2 Gy fraction of 
IMRT for five consecutive days, followed by two days off, for a total of 
approximately seven weeks. Concurrent with study treatment and IMRT, subjects 
will receive cisplatin at a dosage of 80-100 mg/m2 if on a Q3 week schedule or 
30-40 mg/m2 cisplatin if on a weekly cisplatin schedule. Study treatment will 
continue for approximately seven weeks until IMRT completion, patient refusal, 
intolerance, or disease progression. At the end of IMRT, subjects with a WHO 
score ≥ 2 will be followed weekly for up to 8 weeks until the WHO score returns 
to ≤ 1. All patients will enter a post-active phase following the last day of IMRT, 
and will be seen at 3-month intervals for the first year and 4-month intervals for 
the second year. Assessments performed during this post-treatment phase will 
include clinical tumor assessments, complete head and neck exams, tumor 
imaging, and xerostomia and trismus assessments.   
 
 
B. Study Population 
 
The study population will consist of subjects ≥ 18 years of age with a 
pathologically-confirmed diagnosis of squamous cell carcinoma of the head and 
neck (SCC of the oral cavity or oropharynx) that will be treated with cisplatin 
plus IMRT. Patients with unknown primary tumors whose treatment plan 
matches the requirements of the study will be eligible for participation. 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
Galera GT-201 Statistical Analysis Plan, v2.0 
 
Page 14 of 47  
Approximately 216 patients (72 per treatment arm) will be enrolled to achieve 
195 evaluable patients or roughly 65 evaluable patients per treatment arm. Refer 
to Section 7 of Protocol GT-201 for a complete list of the entry criteria for this 
study. 
 
Patients who sign informed consent and meet all eligibility criteria for the trial 
will be assigned a patient number and will be considered enrolled.  Patients who 
are issued a patient number, but who do not successfully complete the screening 
process and who are not randomized into a treatment arm will be considered a 
screen failure.    
 
 
C. Sample Size  
 
The proposed sample size of 216 assumes an early discontinuation rate of 10%, 
yielding approximately 65 patients per arm who will complete their IMRT 
course. This estimated sample size, needed to detect a median reduction in 
duration of 28 days for the treatment arms, relative to subject using placebo, was 
predicted on the basis of the following assumptions:   
 
 Severe OM incidence of 40% in each treatment arm, compared with 65% in 
the control arm 
 Probability of overall type I error (α) of 0.05 
 A null hypothesis that the distribution of duration of severe OM in each 
treatment arm equals the distribution of duration of severe OM in the placebo 
arm. The assumed distribution of duration among all placebo subjects is 
(25th, 50th, 75th percentile): 0, 28, 50 days. 
 An alternative hypothesis that the distribution of duration of severe OM in 
each treatment arm is not equal to the distribution of duration of severe OM 
in the placebo arm. The assumed distribution of duration among subjects in 
each treatment arm is (25th, 50th, 75th percentile): 0, 0, 21 days. 
 Power of at least 80%  
 
D. Treatment Randomization 
 
A permuted fixed-block randomization scheme was created using Proc Plan in 
SAS to assign subjects in a 1:1:1 ratio to one of the three treatment groups (30 
mg GC4419 per day, 90 mg GC4419 per day, Placebo daily).  The scheme was 
stratified by HPV status at baseline (positive vs. negative) and initial 
chemotherapy schedule (q3 weeks vs. weekly cisplatin), without regard to 
investigative site.   After obtaining informed consent and establishing study 
eligibility, the site pharmacist or designee will obtain the study drug assignment 
(one of two GC4419 treatment groups or placebo) using an IXRS system, custom 
designed for the study by Almac. 
 


Galera Therapeutics, Inc. / Protocol: GT-201 
Novella Clinical (Confidential) Project # NXA57202 
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E. Assessment Schedule 
 
The date at which the subject begins treatment with GC4419 (IMRT Day 1) or 
placebo will be referred to as the “start date” or Study Day 1. Subjects will be 
requested to attend a maximum of the following scheduled visits from their start 
date:  weekly, Monday through Friday, beginning at the start date and through 
Study Day 47 (end of IMRT). At the end of the 7 weeks of IMRT (or early 
termination), subjects with a WHO score ≥ 2 will be followed weekly until their 
WHO score is ≤ 1, with an acceptable visit window for weekly assessments of ± 
2 days. Subjects will be considered to have completed follow-up for OM who 
are assessed for OM on or after the completion of IMRT with a WHO score 
≤ 1. 
 
At the end of the Active Phase (7 weeks GC4419/IMRT/Chemo + 8 weeks OM 
assessments, if necessary), the subjects will enter the Post-Active Phase, 
consisting of visits at Months 3, 6, 9, 12, 16, 20, and 24 with an acceptable visit 
window of ± 30 days. Visits that subjects make to the clinic outside the visit 
windows are recorded as unscheduled visits.   
 
V. 
Interventions 
 
A. Clinical Trial Material 
The clinical trial material (CTM) for all subjects will consist of a clear solution 
packaged as an 11 mL ± 0.1mL aliquot in a 10 mL amber glass vial with an S-
127 4432/50 gray stopper and a 20 mm red flip-off seal. The vial contains one of 
the three following constituents: 
 30 mg GC4419: 3 mg/mL in 26 mM sodium bicarbonate-buffered 0.9 wt. 
% saline, Arm A for the entity under investigation 
 90 mg GC4419: 9 mg/mL in 26 mM sodium bicarbonate-buffered 0.9 wt. 
% saline, Arm B for the entity under investigation 
 26 mM sodium bicarbonate-buffered 0.9 wt. % saline, Arm C for placebo 
Subjects will receive an infusion of the CTM daily, Monday-Friday, for 
approximately 7 weeks (up to 35 doses). The protocol provides additional 
information regarding the investigational product, including details on study drug 
supply/storage, study drug administration, and study drug handling/disposal, in 
Section 9.   
 
B. Study Procedures 
 
Refer to Section 11 of the study protocol for a complete list of study assessments 
and procedures. OM assessments will be scored using the WHO OM toxicity 
scale and will be completed at Screening, Baseline, and twice weekly within each 
5-day IMRT period. Additionally, OM assessments will be made weekly for up 


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to 8 weeks after the last day of IMRT for subjects with ulcerative OM (WHO ≥ 
2) until the WHO score returns to 0 or 1. Accompanying procedures for the 
examination of secondary and exploratory outcomes include assessments of 
trismus and xerostomia, data on placement of gastronomy tubes and indwelling 
venous catheters, and blood draws for cytokine levels and RNA analysis.     
 
A Schedule of Events table is provided in Appendix 1. 
 
VI. 
General Analytical Considerations 
 
A. Data Sources 
 
Clinical Data 
Most clinical study data will be entered by the clinical site in an electronic data 
capture system via electronic case report forms (eCRFs). Central laboratory and 
PK results will be received via electronic data transfers and integrated into the 
clinical database for analysis. Biomarkers of mucositis will be measured from 
blood samples collected during the active phase of the study and integrated into 
the clinical database via electronic data transfers. In addition, gene expression 
patterns in patients who consent to the collection of RNA samples will also be 
received via data transfers and integrated into the clinical database. Local 
laboratory data, if performed during an unscheduled visit, will be entered into the 
eCRFs if the local labs support an applicable AE per protocol. 
 
Patient Reported Data 
Xerostomia assessments, use of narcotic medications, and answers to the OMDQ 
will be recorded by the patient on paper forms, which will be subsequently 
entered into the eCRFs by the site. 
 
Randomization Data 
The randomization data and clinical drug supply information will be managed by 
Almac.  Since these data are unblinded, only authorized team members will be 
given access to these files for integration with the clinical study data for the 
production of the interim unblinded data summaries for the DMC.  Once the 
study is completed, these data will be fully integrated with the clinical study data. 
 
Section 17 of the protocol provides additional details regarding data recording 
and handling.   
 
B. Definition of Baseline 
 
Study Day 1 will be designated as the first day a patient receives GC4419 
(Placebo) and will be defined as baseline.  For most measurements, baseline labs 
will be taken pre-dose on Day 1.  If pre-dose assessments on Day 1 are not 
available, the screening result closest to Day 1 may be substituted in some cases.  
Such substitutions will be noted in the clinical study report. The first dose of 


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Cisplatin may be administered before the first dose of GC4419 (Placebo), and 
will not be considered in the definition of baseline. 
 
 
C. Missing Data 
 
Every attempt will be made by the sites to enter complete dates for assessments 
performed during the study. In the event that an adverse event has an incomplete 
start date, the following rules will be used to determine treatment emergence: 
 If complete date is missing, set to date of first dose of GC4419; 
 If year is missing, set year to the year portion of the first dose date of 
GC4419. 
 If the day is missing, set day to the first day of the month or the first dose 
date of GC4419, whichever is later. 
 If the month is missing, set month to the first month of the year or the first 
dose date of GC4419, whichever is later. 
 
With the exception of WHO OM scores, all other data will be reported as they 
are collected; no imputation methods will be used to replace missing data. The 
imputation of WHO OM scores for subjects who lack WHO OM scores, who 
discontinue from the trial without complete follow-up, or whose resolution date 
of severe OM is unknown will be discussed in the relevant sections below.  
 
D. Multiple Study Centers 
 
No adjustment for stratification by the study centers is planned. 
 
E. Covariate Adjustment  
 
The primary and secondary efficacy analyses will be stratified by the two 
stratification factors as entered at randomization, HPV status at baseline and 
planned chemotherapy schedule, resulting in 4 strata. Should any of the four 
strata have fewer than 4 subjects, the analysis will combine over HPV status for a 
given chemotherapy schedule. For example, should the HPV-positive/weekly 
cisplatin stratum have fewer than 4 subjects, the analysis will combine the 
HPV-positive/weekly cisplatin and HPV-negative/weekly cisplatin into a single 
weekly cisplatin stratum, resulting in the analysis having 3, rather than 4 strata 
(namely, a. weekly cisplatin, b. HPV-positive/q3 week cisplatin, and c. 
HPV-negative/q3 week cisplatin). 
 
A few subjects entered the trial with unknown HPV status; subjects with 
oropharyngeal tumors were randomized as HPV positive, while those with oral 
cavity tumors were randomized as HPV negative. 


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F. Interim Analyses or Timing of Analyses 
 
No formal interim analysis is planned for this study. However, as discussed in the 
Statistical Alignment Meeting, a review of unblinded safety data will be 
conducted periodically by a Data Monitoring Committee (DMC), with the first 
review occurring after approximately 45 subjects have completed the 7 week 
GC4491/IMRT/Chemotherapy active treatment phase. Subsequent DMC reviews 
will be held at intervals determined by the DMC. Results from this data review 
could result in recommendations regarding continuing enrollment, holding 
enrollment until further review, amending the protocol, or stopping the study.  
 
The following blinded safety-related data displays will be produced for open 
discussion by the DMC. They may be shared with the project team. These 
displays are summary tables, with the treatment groups aggregated into one 
overall group for display. 
 
 Randomization of Analysis Populations  
 Subject Disposition 
 Demographic and Baseline Characteristics 
 Baseline Disease Characteristics and Prior Treatment 
 Exposure to Study Treatment 
 Exposure to IMRT 
 Exposure to Chemotherapy 
 Study Treatment Modifications and Interruptions 
 IMRT and Chemotherapy Modifications and Interruptions 
 Overall Summary of Treatment-Emergent Adverse Events 
 Summary of Treatment-Emergent Adverse Events by Preferred Term 
 Summary of Treatment-Emergent Adverse Events with CTCAE Grade 
>= 3 by Preferred Term 
 Summary of Serious Treatment-Emergent Adverse Events by Preferred 
Term 
 Summary of Study Treatment Related Treatment-Emergent Adverse 
Events by Preferred Term 
 Summary of IMRT Related Treatment-Emergent Adverse Events by 
Preferred Term 
 Summary of Chemotherapy Related Treatment-Emergent Adverse Events 
by Preferred Term 
 Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Treatment by Preferred Term 
 Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of IMRT by Preferred Term 
 Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Chemotherapy by Preferred Term 


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 Summary of Priority Treatment-Emergent Adverse Events by Preferred 
Term 
 Summary of Treatment-Emergent Adverse Events by Preferred Term and 
Severity 
 Hematology Shift Table for Laboratory Assessments with NCI-CTCAE 
(version 4.03) Toxicity Grades 
 Serum Chemistry Shift Table for Laboratory Assessments with NCI-
CTCAE (version 4.03) Toxicity Grades 
 Summary of Tumor Status 
 
The tables listed above will also be produced for closed discussion by the DMC, 
with the exception that instead of displaying the data in only one aggregated 
group, the data are displayed in three treatment groups, as randomized, plus a 
total group for all patients.  
 
The following data listings will also be provided for the closed session only:  
 
 Randomized Study Eligibility Criteria 
 Treatment-Emergent Adverse Events with CTCAE Grade ≥ 3 
 Serious Treatment-Emergent Adverse Events 
 Treatment-Emergent Adverse Events Leading to Discontinuation of 
Study Treatment, IMRT, or Chemotherapy 
 Treatment-Emergent Adverse Events Leading to Death 
 Priority Treatment-Emergent Adverse Events 
 Vital Signs 
 Hematology 
 Chemistry 
 
G. Test Sizes  
 
Study hypotheses will be tested against two-sided alternatives using a familywise 
Type I error rate (α) of 0.05.   
 
H. Multiple Comparisons 
 
To control the overall Type 1 error at 0.05, the testing of each GC4419 dose 
group to placebo will be done sequentially for the primary and secondary 
endpoints as shown in the following table. Testing will proceed conditional on 
the statistical significance of the prior test(s) at the 0.05 level. 
 
 
Endpoint 
 
Comparison tested at two-sided α = 0.05 
Duration of severe oral mucositis 
(SOM) 
90 mg versus placebo 
↓ 
30 mg versus placebo 


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↓ 
Incidence of SOM through the 30th 
IMRT fraction 
90 mg versus placebo 
↓ 
Incidence of SOM through the end of 
IMRT 
90 mg versus placebo 
↓ 
Incidence of SOM through the 30th 
IMRT fraction 
30 mg versus placebo 
↓ 
Incidence of SOM through the end of 
IMRT 
30 mg versus placebo 
↓ 
Incidence of Grade 4 OM through 
the end of IMRT 
90 mg versus placebo 
↓ 
30 mg versus placebo 
↓ 
Onset of SOM expressed as number 
of IMRT fractions at onset 
90 mg versus placebo 
↓ 
30 mg versus placebo 
 
Under this procedure, duration of severe OM in the 90 mg GC4419 treatment 
arm will be compared with placebo first.  If p≤0.05 for this comparison, duration 
of severe OM in the 30 mg GC4419 treatment arm will be compared.  Additional 
tests of severe OM incidence or other parameters will be performed sequentially 
as long as p≤0.05. If for any test p>0.05, no further hypotheses will be formally 
tested. 
 
I. 
Analysis Populations  
 
Several analysis populations will be defined for use with various analyses.  The 
following table illustrates the relationship between each population and the 
analyses for which the data from the population will be used. 
 
Analysis Population 
Analysis 
Baseline 
Subject 
Disposition 
Efficacy 
Tumor 
Endpoints 
Safety 
PRO 
Health / 
Economic 
Bio-
mark 
ITT 
X   
X 
X 
X 
 
 
 
 
Treated 
   
X 
X 
 
X 
X 
X 
X 
Evaluable 
 
 
X 
X 
 
 
 
 
Per Protocol 
 
 
X 
 
 
 
 
 
 
1. Intent-to-treat Population 
 
The intent-to-treat (ITT) population will include all subjects who are 
randomized and will be used in the primary analysis for all efficacy 
endpoints. Subjects will be analyzed according to their randomized treatment 
assignments.  
 


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2. Treated Population 
 
All randomized subjects who used at least one dose of the CTM will be 
included in the Treated population.  Only subjects with clear documentation 
that no CTM was received may be excluded. Subjects will be analyzed 
according to their randomized treatment, except for analyses of safety and 
tumor endpoints, where analysis will be by the dose received.   
 
3. Evaluable Population 
 
The evaluable population will comprise anyone receiving at least 60 Gy (30 
fractions) of IMRT and at least 25 infusions of CTM. Subjects who are 
retrospectively determined to be ineligible for participation will be excluded. 
 
4. Per Protocol Chemotherapy Population 
 
The per protocol chemotherapy population is defined as the subset of the 
Evaluable population that includes subjects whose chemotherapy consisted 
only of single agent cisplatin including those with dose or scheduled 
modifications and without any substitution of other chemotherapy or 
systemic agents. Subjects who are retrospectively determined to be ineligible 
for participation will be excluded. 
 
PK analyses will be conducted separately and are not included in this Statistical 
Analysis Plan. 
 
J. Data Display Characteristics 
 
Data displays produced for this study will include three types—summary tables, 
data listings, and figures.  Unless stated otherwise, data listings will be produced 
for all recorded data.  Summary tables will be produced as specified in following 
sections.  Additional data listings will be produced for outcome measures that 
involve extensive procedures to derive the analyzed outcomes.  Figures will be 
produced when specified in sections to follow. 
 
Data listings will simply list the data recorded on the CRF or derived for each 
subject.  They will be ordered by treatment, site, subject number, and time of 
assessment.  When expedient, additional levels of ordering hierarchy may reflect 
subsets of assessments within subject.  Data listings will not display subject 
initials. 
 
Summary tables will display summary statistics calculated for each of the 
treatment groups, unless described otherwise in following sections.  Tables may 
have either of two general layouts.  When the greatest interest is in direct 
comparison of one treatment group with the other at particular times, different 
columns of a summary table will display the statistics for the different treatment 


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groups.  The placebo group statistics will be displayed to the right of the 
treatment group statistics.  When the evolution of statistics over time is of greater 
concern than comparison at particular moments, a group of rows may be 
designated for the placebo group; the table columns would be designated for 
different summary statistics of interest.  A subsequent group of rows would then 
be used for the treatment group.  In this layout, a group of rows that represent a 
treatment group would generally be ordered chronologically.  
 
The summary statistics displayed will be a function of the type of data associated 
with the summarized assessment.  Unless stated otherwise in relevant sections to 
follow, continuous data will be summarized with the number of nonmissing 
values, mean, standard deviation (STD), minimum, median, and maximum.  
Categorical data will be summarized with the number of nonmissing values and 
the numbers of values equal to each of the possible values.  Percentages of 
subjects with each of the possible values will be calculated from the number of 
subjects in the corresponding analysis population, unless stated otherwise.  Some 
continuous variables may also be grouped into categorical levels and evaluated in 
frequency tables. 
 
 
K. Blinded Review of Data 
 
After all study data have been collected but prior to examining any study 
outcome data by treatment group, the data may be reviewed by the study team to 
determine whether any clarifications of the analysis plan are needed.  Any 
revisions made to the analysis plan as a result of the blinded review of the data 
will be documented.  Treatment assignments will be unblinded at the time of 
DMC analyses as well as the final analysis. 
 
The date of each unblinding event will be documented in the final study report. 
 
 
L. Balance of Treatment Assignments 
 
The balance of the treatment arms with respect to the randomization strata will be 
evaluated to assess the impact of mis-stratification errors that may occur at the 
time of randomization.  In the event that the treatment assignments appear 
unbalanced across randomization strata, sensitivity analyses of the primary 
and/or secondary endpoints may be conducted using the actual stratification 
values at randomization rather than the stratification values as randomized to 
assess the impact of mis-stratification. 
 
 
VII. Subject Accountability 
 


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A. Subject Characteristics 
 
Demography and Baseline Characteristics.  Data collected about the following 
subject characteristics at the screening visit will be summarized for the ITT 
population: 
 Age.  Age will be calculated as the number of years elapsed between birth 
date and the date of randomization, adjusted for whether the birthday has 
passed as of the day of randomization.  (This corresponds to the typical 
calculation of age a person would use in conversation.) 
 Race 
 Ethnicity 
 ECOG performance status 
 Height and Weight 
 Body Mass Index (BMI) 
 Body Surface Area (BSA) 
 Past and Current Tobacco Use 
 Past and Current Alcohol Use 
Baseline Disease Characteristics.  SCC Cancer Histories collected at the 
Screening visit will be summarized for the ITT population: 
 Months since Initial Histopathological Diagnosis 
 Tumor Location 
 Prior Surgery for SCC Cancer 
 Time Since Prior Surgery 
 Prior Radiation Therapy 
 Prior Systemic Cancer Therapy 
In addition, the following disease characteristics will be summarized for each 
tumor location separately: 
 HPV Status (positive or negative) 
 Primary Tumor Staging 
 Regional Lymph Node Staging 
 Distant Metastasis Staging 
 Anatomic Staging/Prognostic Groups  
 
Medical History.  Medical Histories not related to cancer will be listed for the 
ITT population.  
 


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B. Disposition 
 
A summary of patients in the ITT population will display the numbers and 
percentages of patients in each of the analysis populations, by treatment 
assignment and overall. The numbers and percentages of patients in the ITT 
population will also be presented by each of the stratification factors, HPV status 
and Chemotherapy schedule, both combined and separately. 
 
A summary of patient disposition will summarize the numbers of patients in the 
ITT population who were treated by the length of time they were on-treatment, 
both during the active IMRT/Study Drug treatment period and the Active OM 
Follow-up period. The number and percent of patients who were seen at each of 
the post-active phase visits will also be presented up to the end of the 24-month 
follow-up period. For patients who do not receive at least 60 Gy of IMRT, the 
reasons for treatment discontinuation will be summarized. Reasons for early 
discontinuation from treatment will include the following: 
 Permanent Withdrawal of Consent during the Active Phase 
 Adverse Event 
 Death 
 Disease Progression 
 Investigator Decision 
 Lost to Follow-Up 
 Medical Requirement for Prohibited Medication 
 Patient Non-Compliance 
 Sponsor Decision 
 Early Termination of Study 
In addition, the number and percentage of patients who are no longer on study 
will be summarized by reason: 
 Completed Study 
 Randomization Failure 
 Adverse Event 
 Death 
 Termination of Study 
 Disease Progression 
 Investigator Decision 
 Lost to Follow-Up 
 Medical Requirement for Prohibited Medication 


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 Patient Non-Compliance 
 Permanent Withdrawal of Consent 
 Sponsor Decision 
 
Percentages of subjects who discontinued treatment or withdrew from study for 
each of the above reasons will be calculated using the number of patients in the 
relevant treatment group as the denominator. 
 
This summary will also be produced for the Treated population if more than 5% 
of subjects in the ITT population are excluded from the Treated population. 
 
C. Protocol Deviations and Population Inclusions 
 
A listing will identify subjects who were enrolled even though they did not meet 
one or more eligibility criteria, and subjects who met withdrawal criteria 
discernible from recorded data during the study but were not withdrawn.  Criteria 
for the latter group of subjects will be established at the time of the blinded data 
review. 
 
Protocol deviations will be tracked outside of the electronic data capture (EDC) 
system, and reviewed by the medical monitor. A listing of protocol deviations for 
all enrolled subjects will be produced, and will include the following deviations: 
violations of the treatment plan, eligibility and/or withdrawal violations, omitted 
safety and efficacy assessments, and other unanticipated problems. 
 
VIII. Efficacy Analyses  
 
Efficacy analyses will use data from the ITT population as the primary basis for 
assessing the relative effect of each dose group relative to placebo.  Efficacy analyses 
will also be generated for the treated, evaluable and per protocol chemotherapy 
analysis populations. 
 
A. Efficacy Outcomes 
 
1. Primary Efficacy Outcome 
 
Duration of Severe OM. Duration of severe OM is defined as the number of 
days from the first occurrence of WHO Grade 3 or 4 OM through the first 
occurrence of non-severe (≤ Grade 2) without a subsequent occurrence of ≥ 
Grade 3 OM. Per protocol, subjects are followed for OM post-IMRT weekly, 
for up to 8 weeks or until the OM score is 0 or 1.  Subjects with complete 
follow up of OM who do not develop severe OM will be considered to have 
durations of 0 days. Missing OM data will be imputed based on the following 
rules:  


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 Missing OM scores with two adjacent OM assessments will be assigned 
the poorer of the two adjacent values. 
 Subjects with unknown resolution of severe OM because of loss of 
follow-up for their OM status: Durations with unknown resolution will be 
imputed in descending order from longest duration to shortest duration to 
ensure a complete dataset from which to draw imputations. Subjects will 
have their values imputed with the median duration among all subjects in 
the same treatment arm with at least that observed duration. If no subject 
has at least that duration, the imputed duration will be 15, 30, 60, 75, or 
100 days; the smallest of these values that is greater than the subject’s 
known duration at the time of loss to follow-up will be chosen. See 
Appendix 2 for an example.  
 
 Subjects with loss to follow-up for severe OM who do not develop OM 
while under observation: Imputation will be performed in descending 
order from longest length of follow-up to shortest. Duration of OM will be 
imputed with the median duration among subjects within the same 
treatment group who are free of severe OM for at least that length of 
follow-up. See Appendix 3 for an example. If no subject in the treatment 
group has at least that length of follow-up without severe OM, the imputed 
duration will be 0 days.  
 
2. Secondary Efficacy Outcomes 
 
Cumulative Incidence of Severe OM. The following measures of cumulative 
incidence of severe OM will be analyzed as secondary efficacy outcomes: 
 Any occurrence of WHO Grade 3 or 4 OM from the first IMRT fraction 
through the 30th IMRT fraction. Subjects with loss to follow-up for OM 
before the 30th IMRT fraction will be analyzed according to their imputed 
durations for Grade 3 or 4 OM with onset through the 30th IMRT fraction; 
that is, such subjects with imputed durations greater than 0 days will be 
considered to have severe OM in the analysis of incidence. Imputation of 
duration through the 30th IMRT fraction will use a similar approach as 
imputation of duration for the primary analysis, except that it will only 
consider onset and durations of severe OM through the 30th IMRT 
fraction. 
 Any occurrence of WHO Grade 3 or 4 OM from the first IMRT fraction 
through the last IMRT fraction. Subjects with loss to follow-up for OM 
before the last IMRT fraction will be analyzed according to their imputed 
durations of Grade 3 or 4 OM with onset through the last IMRT fraction; 
that is, subjects with imputed durations greater than 0 days will be 
considered to have severe OM in the analysis of incidence. Imputation of 
duration through the last IMRT fraction will use a similar approach as 


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imputation of duration for the primary analysis, except that it will only 
consider onset and durations of severe OM through the last IMRT fraction. 
 Incidence of WHO Grade 4 OM from the first IMRT fraction through the 
last IMRT fraction. Subjects with loss to follow-up for OM before the 
planned final IMRT fraction will have duration and incidence of Grade 4 
OM imputed as described above. 
 Onset of Severe OM. The onset of severe OM will be measured using 
time-to-event methods using the cumulative IMRT fractions delivered at 
onset of Grade 3 or 4 OM in lieu of calendar time. Those without severe 
OM will be censored at their last assessment for OM. 
The onset of severe OM will also be examined using the following 
measures: 
 Time to onset of severe OM, defined as the number of days from the 
first IMRT to onset of Grade 3 or 4 OM. 
 Cumulative IMRT dose delivered at onset of Grade 3 or 4 OM. 
Those without severe OM will be censored at their last assessment for 
OM. 
 
3. Exploratory Efficacy Outcomes 
 
Duration of Severe OM in Subjects With Severe OM. Duration of severe OM 
is defined as the number of days from the first occurrence of WHO Grade 3 or 
4 OM through the first occurrence of non-severe (≤ Grade 2) without a 
subsequent occurrence of ≥ Grade 3 OM. Per protocol, subjects are followed 
for OM post-IMRT weekly, for up to 8 weeks or until the OM score is 0 or 1.  
Subjects with complete follow up of OM who do not develop severe OM will 
be excluded. Missing OM data will be imputed based on the following rules: 
 
 Missing OM scores with two adjacent OM assessments will be assigned 
the poorer of the two adjacent values. 
 Subjects with unknown resolution of severe OM because of loss of 
follow-up for their OM status: Durations with unknown resolution will be 
imputed in descending order from longest duration to shortest duration to 
ensure a complete dataset from which to draw imputations. Subjects will 
have their values imputed with the median duration among all subjects in 
the same treatment arm with at least that observed duration. If no subject 
has at least that duration, the imputed duration will be 15, 30, 60, 75, or 
100 days; the smallest of these values that is greater than the subject’s 
known duration at the time of loss to follow-up will be chosen. See 
Appendix 2 for an example.  
 Subjects with loss to follow-up for severe OM who do not develop OM 
while under observation will be excluded. 


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Onset of Severe OM in Subjects with Severe OM. The onset of severe OM will 
be measured using time-to-event methods using the cumulative IMRT 
fractions delivered in lieu of calendar time. Those without severe OM will be 
excluded. 
The onset of severe OM will also be examined using the following measures: 
 Time to onset of severe OM, defined as the number of days from the first 
IMRT to onset of Grade 3 or 4 OM. 
 Cumulative IMRT dose delivered at onset of Grade 3 or 4 OM. 
Those without severe OM will be excluded. 
Instances of SOM Lasting ≥ 7 Days. The number of instances of severe OM 
lasting 7 days or longer is defined as the number of instances where severe 
OM is recorded for two or more consecutive assessments during IMRT and/or 
at least one post-IMRT assessment. OM scores resulting from the imputation 
for missing intervening values will be counted. 
Cumulative Incidence of Severe OM. The following measures of cumulative 
incidence of severe OM will be analyzed as exploratory efficacy outcomes: 
 Any occurrence of WHO Grade 3 or 4 OM from the first IMRT fraction 
through the end of post-IMRT early follow-up. For subjects who do not 
have WHO Grade 3 or 4 OM observed prior to loss of follow up, and who 
have incomplete follow-up for severe OM, incidence will be assigned 
using the the imputed duration for the primary analysis.  In the event that 
the imputed duration for the primary analysis is 0, the subject will not be 
considered  to have  WHO Grade 3 or 4 OM through the end of post-
IMRT early follow-up. 
 Any occurrence of WHO Grade 3 or 4 OM from the first IMRT fraction 
through cumulative delivery of 20-29, 30-39, 40-49, or 50-59 Gy of 
IMRT. Imputation of incidence for subjects lost to OM follow-up will not 
be used in this analysis. 
 
AUC. AUC is defined for each subject as the area under the OM-severity vs. 
cumulative IMRT dosage curve. Truncated AUCs will be imputed as 
described above for duration of severe OM (Section VIII.A.1). 
Severe OM Prior to Week 6, Visit 2. The number and percentage of patients 
with severe OM on more than one visit prior to Week 6, Visit 2 will be 
examined. 
Total Number of Severe OM Days. The total number of severe OM days is 
defined as the total number of days per patient of Grade 3 or 4 OM through 
the end of IMRT.  Missing or partially missing days of severe OM will be 


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imputed as described above for duration of severe OM through the end of 
IMRT (Section VIII.A.1). 
Cumulative Incidence, Onset, and Duration of Ulcerative OM.  Ulcerative 
OM is defined as OM with WHO grade of 2 or higher. The cumulative 
incidence, onset and duration of ulcerative OM will be defined as above for 
severe OM (Section VIII.A.1 and VIII.A.2). Missing data will be imputed as 
described for these endpoints in Section VIII.A.1. 
B. Primary Efficacy Outcome Analysis 
 
1. Primary Analysis 
 
The primary assessment of efficacy will use a nonparametric approach. The 
van Elteren test will be used to test the null hypothesis of no difference in 
duration of severe OM between each active arm and placebo. The analysis 
will be stratified by the randomization strata, HPV status and chemotherapy 
schedule. The non-parametric van Elteren test combines the stratum-specific 
Wilcoxon rank-sum statistics with weights inversely proportional to stratum 
sizes. The van Elteren test carried out using the ITT population will be 
considered the primary test of GC4419 efficacy.  
 
The duration of severe OM will be described by presenting overall incidence 
of severe OM and the percentiles of duration by treatment group for all 
patients in the selected analysis population. 
 
2. Sensitivity Analyses 
 
The primary analysis of duration of severe OM for the ITT and Treated 
populations imputes duration for subjects with incomplete follow-up for OM 
with the median observed duration among subjects in the same dose group as 
described in Section VIII.A.1. Because missing data will be imputed only 
once with other observed values in the dataset, the variability of duration in 
the primary analysis may be less than it otherwise would have been had 
complete follow-up for OM occurred in all subjects.  
 
To assess the impact of the primary analysis’ single imputation of missing 
data the clinical study report will include the following sensitivity analysis 
for the ITT population: 
 


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1. 
For each subject with incomplete follow-up, the analysis will impute 
duration by substituting the duration through random selection of a 
subject in the imputation set, rather than selection of the median as 
specified for the primary analysis. If no such subject exists, the analysis 
will randomly select a duration from the uniform distribution between 
the censored duration for the subject being imputed and 75 days.  
2. 
Using the observed and imputed durations selected in Step 1, perform 
the van Elteren test, stratified by HPV status and cisplatin schedule at 
randomization. 
3. 
Perform Steps 1 and 2 100 times. 
  
The reported test for the sensitivity analysis will be median of the 100 
calculated p-values. The range and 25th and 75th percentiles of the van 
Elteren test p-values will also be reported.  
 
C. Secondary Efficacy Outcome Analysis 
 
Cumulative Incidence of Severe OM. Incidence endpoints will be analyzed using 
the Cochran-Mantel-Haenszel test stratified by the factors used in randomization. 
Onset of Severe OM. Cumulative IMRT fractions to onset of severe OM will be 
described for each treatment group and placebo using Kaplan-Meier estimates. 
Subjects without severe OM will be censored at their last OM assessment. 
Estimates of median fractions of IMRT at onset will be summarized for each 
treatment group separately. Estimates of the 25th and 75th percentiles will also be 
included. Groups will be formally tested using a stratified log-rank test. 
On an exploratory basis, analyses will also be generated for time in calendar days 
relative to IMRT start and for cumulative IMRT dose delivered at onset of severe 
OM. 
 
D. Exploratory Efficacy Analyses 
 
Duration of Severe OM in Subjects with Severe OM. The duration of severe OM 
in subjects with severe OM will be described by presenting overall incidence of 
severe OM and the percentiles of duration by treatment group. 
 
Onset of Severe OM in Subjects with Severe OM. Cumulative IMRT dosage to 
onset of severe OM will be described using Kaplan-Meier estimates. Subjects 
without severe OM will be excluded. Estimates of median IMRT at onset will be 
summarized for each treatment group separately. Estimates of the 25th and 75th 
percentiles will also be included. Analyses will also be generated for time in 
calendar days relative to IMRT start and for number of IMRT fractions delivered 
at onset of severe OM. 
 
Instances of Severe OM Lasting ≥ 7 Days. The following two analyses will be 
generated to compare severe OM durations that last seven or more days across 
treatment groups: 


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 The number of instances of severe OM lasting seven or more days will be 
described using descriptive statistics.  
 The proportion of subjects with at least one episode of severe OM lasting 
seven or more days will be presented.  
 
Analyses of Cumulative Incidence of Severe OM. Cumulative incidence of severe 
OM will be compared across treatment groups by presenting the number and 
percent of subjects with any occurrence of WHO Grade 3 or 4 OM through the 
end of post-IMRT follow-up and through cumulative delivery of 20-29, 30-39, 
40-49, and 50-59 Gy of IMRT.  
 
Analyses of Duration and Cumulative Incidence of Grade 4 OM. The duration 
and cumulative incidence of Grade 4 OM from the first IMRT fraction through 
the last IMRT fraction will be presented using descriptive statistics. 
 
AUC Analyses.  AUCs of the OM-severity vs. cumulative IMRT dose curves will 
be compared across treatment groups using descriptive statistics.  
 
Severe OM Prior to Week 6, Visit 2. The number and percentage of patients with 
severe OM on more than one visit prior to Week 6, Visit 2 will be listed and 
summarized with descriptive statistics as a potential way of characterizing 
response to treatment. 
 
Total Number of Severe OM Days. The total number of severe OM days through 
the end of IMRT will be summarized with descriptive statistics and presented in 
a box and whisker plot by treatment group. 
 
Analyses of Ulcerative OM. The cumulative incidence, onset, and duration of 
OM analyses defined above for severe OM (Grade 3 or 4) will be repeated for 
ulcerative OM (Grade 2, 3, or 4). 
 
 
E. Other Efficacy-Related Summaries 
 
In support of the primary, secondary, and exploratory efficacy outcome analyses, 
additional figures and analyses may be generated, including the following:  
 Swimmers plots -- to allow for a visual comparison of incidence and duration 
of severe OM across treatment groups. Each patient’s OM experience during 
treatment and follow-up is displayed on a separate row, color-coded with 
yellow representing Grade 3 OM and red representing Grade 4 OM. Patients 
will be grouped and presented by treatment assignment. 
 Subgroup analyses for hypothesis generation, based on the following 
subgroups: 
o Baseline HPV status 


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o Chemotherapy schedule 
o Tumor type [oral cavity vs. oropharyngeal] 
o Site for sites enrolling at least 15 subjects 
o Prior SCC surgery vs. no prior surgery 
 
IX. 
Analyses of Tumor Endpoints 
 
Analyses of tumor endpoints will use data from the ITT population. Analyses will be 
generated for the whole population and for the sub-groups defined by tumor type 
(oral cavity tumors and oropharyngeal tumors) and HPV status. Tumor endpoint 
analyses will also be generated for the Evaluable population. 
 
A. Tumor Outcomes 
 
Locoregional Failure. Locoregional failure is defined as clinical or radiographic 
evidence of progressive disease at the primary site (local) or the neck (regional). 
Progression should be confirmed by biopsy, if available. If not, clinically 
assessed and documented progression is acceptable. The presence of a 
locoregional failure is captured on the eCRF TUMOR page. 
 
Distant Metastases. Distant metastases is defined as evidence of disease outside 
of the primary site or neck, and should be confirmed by biopsy where possible. 
Distant metastases are captured on the eCRF TUMOR page. 
 
Second Primary Neoplasm. A solitary, speculated lung mass or nodule is 
considered a second primary neoplasm and is captured on the eCRF TUMOR 
page. 
 
New Cancer. The diagnosis of another malignancy is considered a new cancer 
and is captured on the eCRF TUMOR page. 
 
B. Analysis of Tumor Outcomes 
 
The frequencies of locoregional failure, distant metastases, second primary 
neoplasms, and new cancers will be summarized as the number and percent of 
subjects with each of the protocol-defined timepoints where tumor assessments 
are made. The number and percent of subjects who died are also presented. 
 
In addition, the following time-to-event analyses will be performed using 
Kaplan-Meier analysis: 
 Overall Survival (OS) is defined as the time from initiation of study drug 
until death due to any cause. Patients who remain alive will be censored at 
the last time that the patient is known to be alive. 
 Progression Free Survival (PFS) is defined as the time from initiation of 
study drug until progressive disease or death, whichever comes first. Patients 


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will be censored at the date of their last tumor assessment visit if neither 
progression nor death have occurred, or if the patient has gone on to 
subsequent anti-cancer therapy prior to disease progression. 
 Time to Locoregional Failure is defined as the time from initiation of study 
drug until either local or regional progressive disease has occurred. Patients 
will be censored at the date of their last tumor assessment visit if locoregional 
progression has not occurred, if the patient has gone on to subsequent anti-
cancer therapy prior to locoregional progression, or if the patient dies without 
locoregional progression. 
 Time to Distant Disease is defined as the time from initiation of study drug 
until distant metastasis has occurred or a second primary or new cancer has 
been diagnosed. Patients will be censored at the date of their last tumor 
assessment visit if distant metastasis or a second primary or new cancer has 
not occurred, or if the patient dies or goes on to subsequent anti-cancer 
therapy prior to distant metastasis or diagnosis of a second primary or new 
cancer. 
Median estimates of response time and corresponding 95% Confidence Intervals 
will be presented in descriptive summaries for Overall Survival, Progression Free 
Survival, Time to Locoregional Failure, and Time to Distant Disease. Results 
from Kaplan-Meier analyses will also be presented in figures. 
 
The following exploratory analyses (Uno, 2014) of the time-to-event endpoints 
defined above may also be performed: 
 Ratio (or difference) of t-year event rates. 
 Ratio (or difference) of survival function percentiles. 
 Ratio (or difference) of restricted mean survival times or restricted time lost. 
 
 
X. 
Safety Analyses 
 
Safety analyses will use data from the Treated population.   
 
A. Exposure 
 
1. GC4419 or Placebo 
 
Exposure to GC4419 or Placebo will be assessed with the following 
measurements: 
 cumulative dose; 
 the number of doses received by the patient;   
 the number of weeks the patient is on treatment.   


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The number of doses for each subject will be determined from the dosing 
data entered into the eCRFs on the Study Drug Administration page. These 
per-subject exposure measurements will be summarized with descriptive 
statistics, including n, mean (standard deviation), median, and range.  These 
measures will also be categorized into meaningful groups for the summary 
of the number and percentage of patients in each group. In addition, the 
percent of planned doses received will be calculated as the number of actual 
doses received divided by the number of planned doses, expressed as a 
percent, and summarized using descriptive statistics. The number of planned 
doses will be equivalent to the number of planned IMRT fractions up to a 
maximum of 35. 
 
Modifications and interruptions to GC4419 or Placebo will also be 
summarized by presenting the number and percent of subjects with any 
missed or modified dose by reason. The number of modifications will be 
categorized and summarized. 
 
2. IMRT 
 
Exposure to IMRT will be summarized as the cumulative dose of IMRT 
received in Gy, the number of weeks the patient is on IMRT, and the total 
number of IMRT doses received. The IMRT dosing data will be determined 
from the data entered into the eCRFs on the IMRT Administration page. 
These per-subject exposure measurements will be summarized with 
descriptive statistics, including n, mean (standard deviation), median, and 
range.  These measures will also be categorized into meaningful groups for 
the summary of the number and percentage of patients in each group. In 
addition, the Relative Dose Intensity will be calculated as the actual dose 
divided by the planned dose, as captured on the eCRFs, expressed as a 
percent, and summarized using descriptive statistics. 
 
The number of missed doses of IMRT will be summarized with descriptive 
statistics (n, mean (std), median, minimum, and maximum). The number and 
percent of patients who missed any IMRT dose will also be presented by 
reason. In addition, the number and percent of patients who missed 1, 2-4 or 
5+ consecutive IMRT dose fractions will be presented.  
 
3. Chemotherapy 
 
Exposure to Cisplatin will be summarized separately for each dosing 
schedule as the cumulative dose of Cisplatin received in mg/m2, the number 
of weeks the patient is on Cisplatin, and the total number of Cisplatin doses 
received. The Cisplatin dosing data will be determined from the data entered 
into the eCRFs on the Chemotherapy page. These per-subject exposure 
measurements will be summarized with descriptive statistics, including n, 
mean (standard deviation), median, and range.  These measures will also be 


Galera Therapeutics, Inc. / Protocol: GT-201 
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Galera GT-201 Statistical Analysis Plan, v2.0 
 
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categorized into meaningful groups for the summary of the number and 
percentage of patients in each group. In addition, the Relative Dose Intensity 
will be calculated as the actual dose divided by the planned dose, expressed 
as a percent, and summarized using descriptive statistics. Planned 
cumulative chemotherapy dose will be calculated as the first dose in mg/m2 
multiplied by 3 for subjects on a Q3 schedule and by 6 for subjects on a 
weekly schedule. 
 
Modifications, interruptions, and missed doses of Cisplatin will also be 
summarized by presenting the number and percent of subjects with any 
missed or modified dose by reason. The number of doses missed or replaced 
will be summarized with descriptive statistics. In cases where Cisplatin was 
substituted with another chemotherapeutic agent, the number and percent of 
subjects with a replacement in chemotherapeutic agent will be summarized 
and the new therapy will be listed. 
 
 
B. Adverse Events 
 
AE data are available to Galera from two sources, the eCRFs and the SAE forms. 
While reconciliation will be performed, the production of data summaries and 
listings will use the clinical data collected on the eCRFs.   
 
AEs will be coded using the version 18.0 of MedDRA, associating lower-level 
terms with preferred terms and system organ classes by the primary hierarchy.  
Two sets of AE tables will be generated. The first set will display counts and 
percentages of subjects who reported at least one AE in each system organ class 
represented in the AE data.  Within each system organ class, the tables will 
display the counts and percentages of subjects reporting at least one AE, as 
designated by the preferred terms. The second set of tables will display counts 
and percentages of subjects who reported at least one AE for each preferred term. 
 
 AE summaries will include treatment-emergent AEs (TEAEs), that is, AEs with 
an onset date on or after the date on which CTM was first dispensed, as recorded 
on the AE eCRF. Adverse events that exist before the initiation of study 
treatment but worsen in severity during the study will also be included as 
treatment-emergent.   
 
The summary tables organized by system organ class and preferred term will be 
sorted by decreasing order of frequency of MedDRA system organ class code, 
and then, within that, by decreasing order of frequency of AE preferred term in 
the Total column.  The summary tables organized by preferred term only will be 
sorted by decreasing order of frequency of MedDRA preferred term. 
 
The following AE summaries will be produced: 
 Overall summary of TEAEs 


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 All TEAEs 
 TEAEs related to Study Drug.  This table will include TEAEs with a drug 
relationship of “Possibly Related” or “Related.”  It will also include TEAEs 
with missing drug relationships.  An AE reported by a subject more than once 
will be included in this table if at least one of the drug association 
relationship is one of the relationships listed here and will be represented in 
the most relatedness category. 
 TEAEs related to IMRT.  This table will include TEAEs with a drug 
relationship of “Possibly Related” or “Related.”  It will also include TEAEs 
with missing drug relationships.  An AE reported by a subject more than once 
will be included in this table if at least one of the drug association 
relationship is one of the relationships listed here and will be represented in 
the most relatedness category. 
 TEAEs related to Chemotherapy.  This table will include TEAEs with a drug 
relationship of “Possibly Related” or “Related.”  It will also include TEAEs 
with missing drug relationships.  An AE reported by a subject more than once 
will be included in this table if at least one of the drug association 
relationship is one of the relationships listed here and will be represented in 
the most relatedness category. 
 Serious TEAEs 
 Serious TEAEs related to Study Drug. This table will include serious TEAEs 
with the same constraints as TEAEs related to Study Drug. 
 Serious TEAEs related to IMRT. This table will include serious TEAEs with 
the same constraints as TEAEs related to IMRT. 
 Serious TEAEs related to Chemotherapy. This table will include serious 
TEAEs with the same constraints as TEAEs related to Chemotherapy. 
 TEAEs leading to study drug withdrawal.  This subset includes TEAEs with a 
Study Drug Action Taken of “Drug Permanently Withdrawn.” 
 TEAEs leading to IMRT withdrawal.  This subset includes TEAEs with an 
IMRT Action Taken of “Radiation Permanently Withdrawn.” 
 TEAEs leading to withdrawal of Chemotherapy.  This subset includes TEAEs 
with a Chemotherapy Action Taken of “Drug Permanently Withdrawn.” 
 TEAEs with CTCAE Grade ≥ 3. 
 TEAEs by Severity.  On this table, treatment groups will be subdivided into 
five potential grades of AE severity, based on the CTCAE, version 4.03 — 
Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life 
threatening) or Grade 5 (Death).  TEAEs missing a severity grade will not be 
included.  An AE reported by a subject more than once will be represented in 
the most severe category. 
 Priority TEAEs. This table will include priority TEAEs and toxicities of 
special interest that are listed in the protocol or identified during the DMC 
preparation meetings. They are considered medically relevant for treatment 
oversight, and include the following: Dizziness, Lightheadedness, Grade 3+ 


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Nausea, Grade 3+ Vomiting, Paresthesia, Flushing, Hypotension, 
Thromboembolic events related to IV access, Infections related to IV access, 
Renal events, Tinnitus, Hearing loss, Weight loss, Fatigue, Radiation 
Dermatits, and Dysgeusia. 
 TEAEs by Preferred Term 
 
Summary tables presenting counts of TEAEs will also be generated, organized 
by system organ class and preferred term and by preferred term alone. 
 
The following AE listings will be produced: 
 All TEAEs, sorted chronologically within patient. This listing includes 
preferred term, onset and end time, and other relevant information. 
 TEAEs related to Study Drug. 
 TEAEs related to IMRT. 
 TEAEs related to Chemotherapy. 
 All serious TEAEs. 
 All serious TEAEs related to Study Drug. 
 All serious TEAEs related to IMRT. 
 All serious TEAEs related to Chemotherapy. 
 TEAEs leading to discontinuation of Study Drug. This subset includes 
TEAEs with an Action Taken of “Drug Permanently Withdrawn.” 
 TEAEs leading to discontinuation of IMRT. This subset includes TEAEs 
with an Action Taken of “Radiation Permanently Withdrawn.” 
 TEAEs leading to discontinuation of Chemotherapy. This subset includes 
TEAEs with an Action Taken of “Drug Permanently Withdrawn.” 
 TEAEs with CTCAE Grade ≥ 3. 
 TEAEs resulting in Death. 
 Priority TEAEs. This listing will include priority TEAEs and toxicities of 
special interest that are listed in the protocol or identified during the DMC 
preparation meetings. They are considered medically relevant for treatment 
oversight, and include the following: Dizziness, Lightheadedness, Grade 3+ 
Nausea, Grade 3+ Vomiting, Paresthesia, Flushing, Hypotension, 
Thromboembolic events related to IV access, Infections related to IV access, 
Renal events, Tinnitus, Hearing loss, Weight loss, Fatigue, Radiation 
Dermatits, and Dysgeusia. 
 
 
C. Nausea and Vomiting Adverse Events 
 
The following AE summaries and listings, outlined in a separate data display 
document developed for this study4, will be generated for nausea and vomiting 
(N/V) AEs: 


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 Summary of N/V TEAEs by severity (Grade 1-2, 3, 4, 5), overall and by 
timing of onset (within 24 hours of Cisplatin or on Days 2-5 after Cisplatin).  
  
 Listing of N/V TEAEs. 
 Listing of antiemetic Concomitant Medications. 
 
D. Xerostomia and Trismus 
 
Xerostomia and trismus data will be summarized at Baseline and at the 3, 6, 9, 
12, 16, 20, and 24 Month Post-IMRT Follow-up visits. Descriptive statistics and 
change from baseline will be presented for the measurement of the maximum 
opening of the mouth and the self-reported xerostomia ratings of difficulty 
speaking, difficulty swallowing, mouth dryness, throat dryness, and 
mouth/tongue discomfort.  Data listings of xerostomia ratings and trismus 
measurements will also be generated. 
 
E. Clinical Laboratory Results 
 
Laboratory test results (including hematology and serum chemistry,) and 
abnormal laboratory values will be presented in data listings.  Summaries of 
actual values and changes from baseline will be presented by treatment group for 
each assessment time point, beginning with the Screening visit.  Shift tables 
summarizing the counts and percentages of subjects who were normal at 
baseline, but who became abnormal subsequently, will also be displayed for 
those per-protocol lab parameters that are graded according to the Common 
Toxicity Criteria (CTCAE v. 4.03).   
 
F. Vital Signs 
 
Vital signs (including supine systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature, weight, and body mass index) will be presented in a 
data listing. Body temperature will be collected in °F or °C, but reported in °C.  
Weight will be collected in pounds (lb) or kilograms (kg), but reported in kg. 
 
 
G. Concomitant Medications 
 
Concomitant medications (CMs) will be coded using the latest version of the 
WHO Drug dictionary.  A summary table will be organized to display the 
anatomical main class of each coded CM and, within that, the pharmacological 
subgroup (3rd level) of the coded CM.  The summary table will display counts 
and percentages of subjects who reported using at least 1 CM in each represented 
pharmacological subgroup. 
 


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A listing of CMs will be generated, ordered within subject by the “Start Date.”  
The listing will display the recorded term from the CRF and, adjacent to that, the 
WHO Drug pharmacological subgroup that appears in the tables.  
  
A separate listing of antiemetic CMs, as specified in Appendix 7 of the protocol, 
will also be generated to assess prophylactic use in the treatment of nausea and 
vomiting induced by chemotherapy 
 
H. Electrocardiogram (ECG) 
 
ECG results (VR, PR, QRS, QT, machine-read QTc, manually calculated QTcF 
QTcB, and the overall ECG result) will be presented in data listings.  
 
I. 
ECOG Performance Status 
 
ECOG Performance Status will be presented in data summaries and listings for 
all time points at which it is collected. 
 
 
XI. 
Analysis of Patient Reported Outcomes 
 
The Oral Mucositis Daily Questionnaire (OMDQ) is used to capture daily quality of 
life assessments during the IMRT treatment period, and is recorded daily by the 
patient.  These assessments will be summarized using data from the Treated 
population, and are considered exploratory endpoints.  
 
OMDQ Question 2 will be summarized using descriptive statistics (n, mean (std), 
median, range) for the ratings of overall mouth and throat soreness.  All OMDQ items 
will be presented in a data listing. 
 
XII. Analysis of Health and Economic Outcomes 
 
The assessment of health and economic outcomes includes the incidence and duration 
of opioid use and the insertion of and need for use of gastrostomy tube feeding, 
complications of indwelling venous access catheters, and unplanned hospitalizations, 
ER visits, or office visits. These assessments will be summarized using data from the 
Treated population, and are considered exploratory endpoints. The analysis of these 
endpoints is described in a separate document outlining the data outputs and displays 
for this study4. 
 
The use of gastrostomy tubes and venous access catheters and unscheduled hospital, 
ER or office visits will be summarized according to treatment assignment by 
presenting the number and percent of subjects using each device or medical service. 
Complications of indwelling venous access devices and reasons for unscheduled 
hospital or office visits will be summarized.    
 


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Patient-reported narcotic use will be summarized by treatment assignment by 
presenting the number and percent of patients using opioid narcotics. In addition, 
descriptive statistics (n, mean (std), median, 25th-75th percentiles) will be presented  
for total opioid narcotic dose in morphine equivalents, time to first opioid narcotic 
use, and cumulative IMRT at first opioid narcotic use. 
 
 
XIII. Biomarker Analyses 
 
Biomarker analyses will use data from the Treated population, and will be presented 
by treatment assignment.  
 
A listing of each patient’s circulating cytokine and protein levels will be presented by 
time point. The analysis of cytokines and mRNA with respect to clinical endpoints is 
beyond the scope of this SAP and will be specified at a later date. 
 
 
 
 
 
 
 


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XIV. References 
 
1. Sonis ST. The impact, biology and therapeutic opportunities of oral mucositis. Oral 
Oncol 2009; 45:1015-20. 
 
2. Sonis ST, Elting LS, Keefe D. et al. Perspectives on cancer therapy-induced 
mucosal injuty: pathogenesis, measurement, epidemiology, and consequences for 
patients. Cancer 2004; 100 (9 Suppl): 1995-2025. 
 
3. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT plus weekly 
cisplatin for advanced head and neck cancer: The University of Wisconsin 
experience. Head and Neck 2010: 32:599-606. 
 
4. Holmlund, J. Planning for Galera Phase 2 data displays sept 2015. Unpublished, 
2015. 
 
5. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral  mucositis after 
intensive therapy for hematologic cancers. New Engl J Med 2004; 351: 2590-8. 
 
 
 


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APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Assessments 
Screening 
Phase 
Active Phase 
Post-Active Phase 
Within 28 
days  
of IMRT 
start 
Baseline 
IMRT 
Day 1 
Wk 1 
Days 
2 – 7 
Wk 2 
Days 
8 - 14 
Wk 3 
Days 
15 - 21 
Wk 4 
Days 
22 - 28 
Wk 5 
Days 
29 - 35 
Wk 6 
Days 
36 - 42 
Wk 7 
Days 
43 - 49 
Last Day 
of IMRT 
or Early 
Term1 
Post-
IMRT 
Wks 1 
through 8 
(±2 D)2 
Months 
3, 12, & 
24 Post-
IMRT 
(±30 D) 
Months 
6, 9, 16 & 
20 Post-
IMRT  
(±30 D) 
Informed consent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and HNC histories4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete PE5 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed PE 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Dental exam/IMRT clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, ECOG, weight6 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
Record BSA7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging 9 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Tumor Assessment10 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Concomitant medications11 
X 
X 
Weekdays 
X 
X 
 
 
Adverse Events12 
 
X 
Weekdays 
X 
X 
 
 
ECG (12-lead)13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
OM assessment14 
X 
X 
X 
Twice-weekly 
X 
X 
X 
 
 
Trismus assessment15 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xerostomia assessment16 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
OMDQ, analgesic recording17 
 
X 
Daily including weekends 
X 
X 
 
 
Gastrostomy tube 
placement/use 
 
X 
X 
Twice-weekly 
X 
X 
 
 
 
Unscheduled office visits, ER 
visits, or hospitalizations 
 
 
 
Twice-weekly 
X 
X 
 
 
 
Placement of indwelling venous 
catheters  
X 
 
 
 
Blood draw: Lab safety tests18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
 
 
 
Blood draw: PK samples20 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Blood draw: Cytokines21 
X 
X 
 
OM Visit 2 
 
OM Visit 2 
 
OM Visit 2 
 
X 
 
 
 
Blood draw: RNA22 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Dosing GC441923 
 
X 
Days 
2-5 
Days 
8-12 
Days 
15-19 
Days 
22-26 
Days 
29-33 
Days 
36-40 
Days 
43-47 
 
 
 
 


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1 If a patient ends study participation early and withdraws consent, all last day of IMRT procedures should be completed. 
2 The Post-IMRT Weeks 1 through 8 Follow-up Visits will be scheduled based on the last day of IMRT. Patients will be seen weekly (every 7 ± 2 calendar days) 
until WHO < 2. 
3 See protocol Sections 7.1 and 7.2. 
4 The HNC history should include tumor HPV status (if known), staging (AJCC) information, prior treatments, and confirmation of histopathological diagnosis 
of SCC. Medical conditions and illnesses that have occurred since the patient signed the ICF up until the date of randomization should be recorded as medical 
history. Medical history also includes tobacco and alcohol use history. 
5 At the Screening and Last Day of IMRT Visits, a complete physical examination will be conducted. 
6 Vital signs (temperature, systolic and diastolic blood pressures, heart rate, and respiration rate), body weight, and ECOG will be obtained and recorded at the 
Screening and Baseline Visits, once during Weeks 4 and 7, and at the Last Day of IMRT Visit. All vital signs should be measured following 2 minutes of rest 
in the sitting position. 
7 For patients receiving tri-weekly cisplatin, body surface area (BSA) will be recorded to confirm cisplatin dosing at the Baseline Visit and once during Weeks 4 
and 7. For patients receiving weekly cisplatin, body surface area (BSA) will be recorded to confirm cisplatin dosing at the Baseline Visit and once per week 
until chemotherapy is completed. 
8 For a woman of childbearing potential, serum pregnancy test must be performed at the Screening Visit.  
9 Radiographic imaging must be performed within 60 days prior to the first day of IMRT and at Months 12 and 24 Post-IMRT for all patients. Patients treated 
definitively (as opposed to post-operatively) will also undergo imaging at Month 3 Post-IMRT to assess tumor response/clearance to the degree possible. 
Radiographic imaging is highly recommended at any Post-IMRT follow up visit at which disease progression is suspected by the treating physician. If 
radiographic imaging is performed, both local/regional recurrence and distant metastases should be evaluated.   
10 At the Last Day of IMRT Visit, a clinical tumor assessment will be conducted. A neck and oral exam is sufficient at the Last Day of IMRT Visit if disease 
progression is not suspected. If disease progression is suspected, a laryngopharyngoscopy should be conducted. At Months 3, 6, 9, 12, 16, 20, and 24, a 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required if disease progression is suspected to evaluate local/regional or distant 
progression. 
11 All concomitant therapies (e.g., prescription and over-the-counter medications) taken by patients on or after the date of randomization through 30 days 
following the last GC4419/placebo, IMRT or cisplatin (i.e. whichever occurs last) dose will be collected in the CRF except for narcotics (narcotics will only be 
captured from the Baseline Visit through the Last Day of IMRT Visit).  Additionally, any concomitant therapies used to treat any serious or related adverse 
event will be recorded in the CRF.  
12 AEs and SAEs with onset dates on or after the date of randomization through 30 days following the last GC4419/placebo, IMRT or cisplatin (i.e. whichever 
occurs last) dose will be recorded on the CRF.  All patients with SAEs will be followed until the events resolve, stabilize, become chronic, the patient 
completes the study, or the patient is lost to follow-up. 
13 Ventricular rate and P-R, QRS, QT, and QTc intervals will be assessed and recorded. An ECG will be conducted at the Screening and Baseline Visits, during 
Week 4, and at the Last Day of IMRT Visit.  
14 All OM assessments must be performed by trained evaluators. The extent of the patient’s OM will be scored using the WHO OM toxicity scale. OM 
assessments will be completed at the Screening Visit, at the Baseline Visit, and twice weekly (no less than 48 hours apart) within each 5-day IMRT period. For 
Week 1, the first OM assessment will occur at the Baseline Visit; one additional OM assessment must occur at least 48 hours later during the week. The extent 
of the patient’s OM will be scored using the WHO OM toxicity scale. If a patient has ulcerative OM (WHO ≥ 2) at the Last Day of IMRT Visit, visits for OM 
will be repeated weekly (every 7 days ± 2 days) until the WHO score is 0 or 1 or the patient is 8 weeks post-IMRT, whichever occurs first. 
15 Using a Sponsor-provided ruler, the distance in millimeters between the incisal edges of the mandibular and maxillary incisors at midline will be measured to 
determine the maximum opening of the mouth that the patient can achieve at the Baseline Visit and Months 3, 6, 9, 12, 16, 20, and 24 Post-IMRT Visits.   
16To assess xerostomia, patients will complete a VAS instrument at the Baseline Visit and 3, 6, 9, 12, 16, 20, and 24 Month Post-IMRT Visits.  


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17 Beginning at the Baseline Visit (IMRT Day 1) and through the Last Day of IMRT Visit, patients will complete a daily diary (including weekends) containing 
the OMDQ and questions regarding narcotic use. If a patient returns for weekly visits following the last day of IMRT because WHO ≥ 2, the OMDQ only will 
be completed at the time of the weekly clinic visit.   
18 Clinical laboratory measurements will be conducted at the Screening Visit, twice during Week 1 (once at the Baseline Visit and again on Day 3, 4 or 5), and 
once weekly from Week 2 through the last day of IMRT. Clinical laboratory measurements at these visits will include the hematology profile (hemoglobin, 
hematocrit, red blood cell count, white blood cell count with differential, and platelet count.  Differential to include total neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) and chemistry profile (glucose, BUN, creatinine, sodium, potassium, calcium, albumin, total protein, total bilirubin, direct bilirubin, 
alkaline phosphatase, ALT (SGPT), AST (SGOT), chloride, phosphate, bicarbonate). 
19 If safety labs have already been drawn during the study week in which the last day of IMRT or early termination visit falls, then lab safety tests (chemistry and 
hematology profiles) do not need to be conducted on the last day of IMRT or at the early termination visit.  If safety labs have not been drawn during the 
current study week at the time of the early termination visit or on the last day of IMRT, then safety labs should be drawn on that day.  Safety labs only need to 
be drawn once per study week after Week 1. 
20Blood samples will be collected for GC4419 pharmacokinetic (PK) measurements at Baseline, Day 2, Day 22 and Day 23. See Table 10 in the protocol for 
additional information.  
21For cytokine analysis, blood samples will be collected at the Screening Visit (within 28 days of IMRT start but at least 72 hours prior to Baseline), at the 
Baseline Visit, Week 2 OM Visit 2, Week 4 OM Visit 2, Week 6 OM Visit 2, and at the Last Day of IMRT Visit. Whenever possible, blood draws for cytokine 
analysis should be conducted at OM Visit 2 for each protocol-specified week; however, if blood draws must be taken on another day within a given week, it 
will not be considered a protocol deviation. 
22If the patient consents separately, blood samples will be collected at the Screening Visit (within 28 days of IMRT start but at least 72 hours prior to Baseline) 
and at the Last Day of IMRT Visit for the assessment of gene expression patterns prior to receiving the first dose of GC4419 and upon completion of GC4419 
doses.   
23GC4419 will be administered up to 35 times: weekly, Monday through Friday, beginning at Baseline (IMRT Day 1) and through Study Day 47 (end of IMRT). 
IMRT must begin no longer than 60 min following the end of the GC4419 infusion.  If IMRT is not received on any given day due to a treatment break or 
unforeseen circumstances, GC4419 should not be administered on that day.  Patients should resume GC4419 administration when IMRT resumes. 


Galera Therapeutics, Inc. / Protocol: GT-201 
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APPENDIX 2: HYPOTHETICAL EXAMPLES FOR IMPUTING 
MEDIAN DURATION AMONG SUBJECTS WITH UNKNOWN 
SEVERE OM RESOLUTION  
 
Consider the following dataset, where the first four subjects have known duration of severe 
OM, while the fifth subject’s severe OM, indicated by an asterisk, is known to have 
continued for at least seven days before the subject was lost to follow-up: 
 
Ex. 1. 
Imputing severe OM duration for subjects without OM resolution (part 1) 
Subject 
OM duration  
1 
3 days 
2 
4 
3 
9 
4 
0 
5 
7* 
 
The analysis plan states that the duration should be imputed using the median duration of 
severe OM amongst subjects who experienced severe OM for at least the same duration. In 
this example, it is straightforward, then, to calculate the imputed severe OM duration for 
Subject 5 as 9, the median duration of the only subject (Subject 3) with a duration of at least 
7 days.  
 
If, instead, Subject 5’s duration had been 17 days instead of 7, no subject in the dataset would 
have had OM at least as long as Subject 5. In this case, the analysis plan states to use 15, 30, 
60, 75, or 100 days, whichever is smallest yet still greater than the known duration at the 
point of loss to follow up. In this case, then, we would assign Subject 5’s duration as 30 days. 
 
Suppose we modify the example above such that Subject 3’s duration is censored at 9 days: 
 
Ex. 2. 
Imputing severe OM duration for subjects without OM resolution (part 2) 
Subject 
OM duration 
1 
3 days 
2 
4 
3 
9* 
4 
0 
5 
7* 
 
Now, both Subject 3’s and Subject 5’s duration require imputation. For Subject 5’s 
imputation, we could either use a value of 9 (i.e., Subject 3’s duration at censoring) or 15 
(i.e., Subject 3’s imputed duration using the analysis plan’s conventions). 
 


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The analysis plan states that the longest censored durations should be imputed first and to use 
these imputed values for any subsequent subjects who may require imputation. That is, for 
the situation described above, we would use Subject 3’s imputed value of 15 days to impute 
Subject 5’s duration. Accordingly, in this small example dataset, Subject 5’s duration would 
also be 15.  
 
 
 


Galera Therapeutics, Inc. / Protocol: GT-201 
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APPENDIX 3: HYPOTHETICAL EXAMPLES FOR IMPUTING 
MEDIAN DURATION AMONG SUBJECTS WITHOUT SEVERE OM 
BEFORE LOSS TO FOLLOW 
 
Consider a subject lost to follow-up for severe OM at Day 30 who did not develop severe 
OM during this time. Following imputation of any censored durations as outlined in 
Appendix 2, the dataset in Example 3 includes the 5 subjects in the same treatment group 
who were followed for severe OM for at least 30 days without developing severe OM 
through Day 30. 
 
Ex. 3. 
Imputing severe OM duration for subjects without OM before loss to follow-up 
Subject 
Onset day of OM 
OM duration  
1 
NA 
0 days 
2 
43 
20 
3 
NA 
0 
4 
32 
15 
5 
57 
30 
 
The analysis plan states that the duration is imputed with the median duration among subjects 
within the same treatment group who are free of severe OM for at least that length of 
follow-up. In this example, the median duration among these subjects is 15 days.