Clinical trial NCT03689712
Conditions: Oral Mucositis
Keywords: Oral Mucositis Superoxide Dismutase Mimetic Cisplatin Intensity-Modulated Radiation Therapy Chemoradiation OM IMRT Head and Neck Cancer Squamous Cell Carcinoma SCC Oral Cavity Oropharnyx Mouth Sores avasopasem mangenese
Sponsor: Galera Therapeutics, Inc.
Start date: 2018-10-03; Completion date: 2023-08-25
Enrollment: 455 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the phase 3, clinical study is to determine if GC4419 (avasopasem manganese) administered prior to intensity-modulated radiation therapy (IMRT) reduces the 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:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: GC4419 90mg intervention 2: Placebo
Intervention descriptions: intervention 1: 60 minute IV infusion intervention 2: 60 minute IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol GTI-4419-301 
Galera Therapeutics, Inc. 
Confidential 
Version: Amendment 4 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
ROMAN: Reduction in Oral Mucositis with Avasopasem 
Manganese (GC4419) – Phase 3 Trial in Patients Receiving 
Chemoradiotherapy for Locally-Advanced, Non-Metastatic Head 
and Neck Cancer 
 
 
Sponsor: 
Galera Therapeutics, Inc. 
2 West Liberty Boulevard, Suite 110 
Malvern, PA 19355 USA 
 
 
IND Number: 
111,539 
 
 
Protocol ID: 
GTI-4419-301 
 
 
Medical Monitor: 
Jon T. Holmlund, MD 
 
 
Protocol Version/Date: 
Amendment 4: 13 July 2020 
 
 
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 subjects. 




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1. 
SYNOPSIS 
Name of Sponsor/Company: Galera Therapeutics, Inc.  
Name of Investigational Product: GC4419 (avasopasem manganese) 
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 superoxide dismutase (SOD) enzymes. 
Title of Study: 
ROMAN: Reduction in Oral Mucositis with Avasopasem Manganese (GC4419) – Phase 3 Trial in 
Patients Receiving Chemoradiotherapy for Locally-Advanced, Non-Metastatic Head and Neck 
Cancer 
Number of Study Center(s): 
Approximately 100 sites in the United States and Canada 
Estimated Enrollment Period:  
Approximately 32 months 
Studied Period (years): 
Date first subject enrolled: 3-Oct-2018 
Estimated date last subject enrolled: 2nd quarter 2021 
Estimated date last subject completed Post-IMRT Phase (completion of 
follow up for primary efficacy endpoint): 2nd quarter 2021 
Estimated date for primary efficacy and safety results: 2nd half 2021 
Estimated date last subject completed Long-term Follow-up: 2nd quarter 2023 
Estimated date for tumor outcome results: 2nd half 2023 
Phase of 
development: 3 
Study Period Definitions: 
Study Treatment Period: the period of time from Study Day 1 (IMRT Day 1/Baseline) through the 
last day of IMRT. Subjects who receive at least 60 Gy of IMRT will be considered to have completed 
the Study Treatment Period. 
OM (Oral Mucositis) Observation Period: the period of time from Study Day 1 (IMRT Day 
1/Baseline) through the last OM assessment. By protocol, the last OM assessment is to occur during 
the second week after completion of IMRT. 
AE (Adverse Event) Observation Period: the period of time from the date of randomization 
through 30 days post last day of cisplatin, IMRT, or GC4419/Placebo (i.e., whichever occurs last). 


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LTFU (Long-term Follow-up) Observation Period: the period of time from last day of IMRT 
through 24 months post-IMRT. 
Objectives: 
Primary Objective: 
To assess the effect of GC4419 administered intravenously (IV) on the incidence of severe oral 
mucositis (SOM; Grade 3-4 OM) during the Study Treatment Period in subjects receiving 
post-operative or definitive therapy with single-agent cisplatin plus Intensity-Modulated 
Radiation Therapy (IMRT) for locally advanced, non-metastatic squamous cell carcinoma 
(SCC) of the oral cavity or oropharynx 
Secondary Objectives: 
To assess the effect of GC4419 administered intravenously (IV) on the incidence of Grade 4 OM 
during the Study Treatment Period in subjects receiving post-operative or definitive therapy 
with single-agent cisplatin plus Intensity-Modulated Radiation Therapy (IMRT) for locally 
advanced, non-metastatic squamous cell carcinoma (SCC) of the oral cavity or oropharynx 
To assess the effect of GC4419 administered intravenously (IV) on the total number of days of 
Grade 3-4 OM during the OM Observation Period in subjects receiving post-operative or 
definitive therapy with single-agent cisplatin plus Intensity-Modulated Radiation Therapy 
(IMRT) for locally advanced, non-metastatic squamous cell carcinoma (SCC) of the oral 
cavity or oropharynx 
To assess the effect of GC4419 administered intravenously (IV) on the total number of days of 
Grade 4 OM during the OM Observation Period in subjects receiving post-operative or 
definitive therapy with single-agent cisplatin plus Intensity-Modulated Radiation Therapy 
(IMRT) for locally advanced, non-metastatic squamous cell carcinoma (SCC) of the oral 
cavity or oropharynx 
To confirm safety and tolerability of GC4419 administered IV in subjects receiving cisplatin plus 
IMRT for locally advanced, non-metastatic SCC of the oral cavity or oropharynx 
To evaluate potential effects of GC4419 on tumor efficacy outcomes for the study population 
Endpoints: 
Primary Endpoint: 
Cumulative incidence of SOM, defined as the proportion of subjects with any occurrence of 
WHO Grade 3-4 OM, during the Study Treatment Period 
Secondary Endpoints: 
Efficacy: 
Cumulative incidence of WHO Grade 4 OM, defined as the proportion of subjects with any 
occurrence of WHO Grade 4 OM, during the Study Treatment Period 
Total number of days (per subject) of SOM (WHO Grade 3-4) during the OM Observation Period 
for all subjects 
Total number of days (per subject) of Grade 4 OM during the OM Observation Period for all 
subjects 


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Safety: 
Safety of GC4419 as measured by: 
− 
Frequency, duration, and severity of adverse events (AEs) and serious AEs (SAEs) 
during the AE Observation Period; 
− 
Incidence and shifts of clinically significant laboratory abnormalities 
Effect of treatment on tumor outcomes (locoregional failure, distant metastases, progression-free 
survival, overall survival) during the LTFU Observation Period 
Methodology: 
GTI-4419-301 is a randomized, double-blind, placebo-controlled, multi-center international study 
conducted to evaluate GC4419 administered IV to reduce the incidence and severity of radiation-
induced SOM in subjects receiving chemoradiation for squamous cell carcinoma of the head and neck 
(SCCHN), limited to the oral cavity or oropharynx. Subjects will be randomized in a 3:2 ratio to 1 of 
2 treatment arms: 
Arm A: 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 100 mg/m2 once every three weeks for 3 
doses or 40 mg/m2 once weekly for 6-7 doses (Investigator’s choice) 
Arm B: 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 100 mg/m2 once every three weeks for 3 
doses or 40 mg/m2 once weekly for 6-7 doses (Investigator’s choice) 
Enrollment will be stratified at randomization for 2 factors: cisplatin schedule (weekly vs q3week); 
post-operative vs definitive treatment. 
Note: Planned radiation fields in both arms must include at least 2 oral sites (left and right buccal 
mucosa, floor of mouth, left and right ventral/lateral tongue, soft palate) with each site receiving a 
cumulative dose of at least 50 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. 
All subjects will be assessed twice weekly for OM per WHO grading criteria until the end of the 
study treatment period (last day of IMRT), and once weekly thereafter for 2 weeks. 
The study will be monitored by a Data Monitoring Committee (DMC). 
PK sampling will be sought from all subjects. 
Number of Subjects (planned): 
Approximately 450 total subjects, 270 in the GC4419 arm and 180 in the Placebo arm, will be 
enrolled from investigational sites in the US and Canada. 
 
 
 


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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. 
Note: Patients with unknown primary tumors whose treatment plan matches the requirements 
specified in Inclusion Criteria #2 and #3 below are eligible for the study. 
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 of 60-72 Gy. Planned radiation treatment 
fields must include at least two oral sites (left and right buccal mucosa, floor of mouth, left 
and right ventral/lateral 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 constitute 
planned radiation. 
3. Treatment plan to receive standard cisplatin monotherapy administered either every three 
weeks (100 mg/m2 for 3 doses) or weekly (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  upper-normal limit (ULN) 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5  ULN 
− 
Alkaline phosphatase ≤ 2.5  ULN 
8. Serum pregnancy test negative for females of childbearing potential 
9. Males and females must agree to use effective contraception starting prior to the first day of 
treatment and continuing after the last dose of GC4419/Placebo for 30 days (females) or 90 
days (males) 
10. Properly obtained written informed consent 
 


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Exclusion Criteria: 
1. Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands 
2. M1 disease (distant metastasis) 
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) 
4. Prior induction chemotherapy for current HNC or any prior immunotherapy 
5. Receiving any approved or investigational anti-cancer agent other than those provided for in 
this study 
6. Concurrent participation in another interventional clinical study or use of another 
investigational agent within 30 days of first dose of GC4419/Placebo 
Note: Patients who are participating in non-interventional clinical studies (e.g., QOL, imaging, 
observational, follow-up studies, etc.) are eligible, regardless of the timing of participation. 
7. Inability to eat soft solid food at baseline for reasons other than mouth soreness after surgery 
or dental procedures 
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 head and neck cancer (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 at baseline. Subjects with mouth or throat pain solely due to post-
operative effects are eligible, however. 
12. Known history of human immunodeficiency virus (HIV) or history of 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 9 mg/mL (Arm A) in 26 mM sodium 
bicarbonate-buffered 0.9 wt. % saline for parenteral administration (drug product). The GC4419 
solution may appear clear or have a slight yellowish tint. GC4419 will be presented in 35 single use 


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amber vials, one vial per day. Vials will be filled with 11 mL of GC4419, of which 10 mL will be 
added into a 250 mL bag of normal saline, for daily IV administration over 60 minutes.  
Although solutions should be free of particulates, it is possible that some vials may have some fine 
visible particulates. Infusions must be prepared using a sterile 0.2 or 0.22 micron syringe filter prior 
to introduction into the infusion bag or a sterile 0.2 or 0.22 micron inline filter must be used during 
IV administration.  
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 100 mg/m2 once every three weeks for 3 doses or 40 
mg/m2 once weekly for 6-7 doses (Investigator’s choice). 
Duration of Treatment: 
Approximately 35 doses, on days in which IMRT is administered, Monday-Friday (M-F), 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 B). 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 
100 mg/m2 once every three weeks for 3 doses or 40 mg/m2 once weekly for 6-7 doses (Investigator’s 
choice). 
Criteria for Evaluation: 
Efficacy: 
WHO Criteria for OM 
Safety: 
National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0 
Clinical Laboratory Assessment: A central laboratory vendor will be utilized. 
DMC Review 
Toxicity Management: 
Toxicity requiring 25% GC4419 or Placebo dose reduction: 
Grade 2 or greater hypotension within 2 hours after the start of GC4419/Placebo infusion (i.e., 
anytime from start of infusion through 1 hour after end of infusion). 
The dose of GC4419 or Placebo may be reduced by 25% for Grade 3-4 adverse events (AEs) judged 
by the Investigator to be likely attributable to the study infusion. 
Two dose reductions for toxicity will be permitted per subject. Subjects unable to tolerate 
GC4419/Placebo after 2 dose reductions must discontinue treatment with GC4419/Placebo but should 
continue with cisplatin/IMRT and other study assessments and procedures, with the concurrence of 
the treating Investigator, if the subject maintains informed consent to do so. 
For other toxicities (including those attributable to cisplatin and IMRT): management per institutional 
and American Society of Clinical Oncology (ASCO) guidelines and Investigator judgment. Cisplatin 


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toxicities should be managed by modification of the cisplatin dose and schedule, not by substitution 
of another systemic agent. 
Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral 
Oncology (ISOO) Oral Care Education Materials and patient instructions for oral hygiene will be 
strongly recommended, and a summary appended to the protocol (Appendix 6). 
OM will NOT be considered an AE 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®, Pharixia®, Tantum Verde) 
Cetuximab (Erbitux®) 
Glutamine in any form 
GM-CSF applied topically 
‘Magic mouthwashes’ or ‘Miracle mouthwashes’ are permitted, provided they do not contain: 
− 
Chlorhexidine 
− 
Hydrogen peroxide 
− 
Diphenhydramine (Benadryl®) liquid formulation 
− 
Tetracycline 
− 
Any other listed disallowed medications 
− 
Notes: 
o Topical lidocaine preparations are permitted 
o Diphenhydramine (Benadryl®) administered as tablets or by injection is 
permitted 
MuGard™, Gelclair®, Episil®, or other barrier devices 
Caphosol® 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildenafil, tadalafil, or similar agents) 
or other drugs that in the judgment of the treating Investigator could create a risk of a 
precipitous decrease in blood pressure are prohibited 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 


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Steroid rinses 
Sucralfate in suspension form (use of sucralfate tablets is permitted) 
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 or perceived herbal/homeopathic or other remedies for OM, which 
are considered investigational for purposes of this study (includes nitric oxide) 
All medication restrictions begin on Day 1 of IMRT and GC4419/Placebo. 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. 
Oral care per MASCC/ISOO Oral Care Education Materials (summarized in Appendix 6) will be 
strongly recommended for all subjects as part of standard of care. 
Statistical Methods: 
Approximately 450 subjects will be enrolled (270 GC4419:180 Placebo) to obtain approximately 400 
Intent-to-Treat (ITT) subjects (240 GC4419:160 Placebo). The proposed ITT sample size of 400 
assumes that 10% will discontinue early, yielding approximately 216 subjects in the experimental 
arm and approximately 144 in the Placebo arm who will complete their IMRT course. The study will 
have approximately 95% power to detect a relative reduction in incidence of severe OM throughout 
the study treatment period in the experimental arm of approximately 34% compared to Placebo (43% 
incidence for GC4419 vs 65% for Placebo). 
Safety and efficacy will be assessed on the ITT population consisting of all randomized subjects who 
receive at least one dose of GC4419/Placebo, excluding the 28 subjects whose dosing was interrupted 
due to the Sponsor’s dosing suspension decision. 
Analysis of incidence/proportion endpoints will use the Cochran-Mantel-Haenszel (CMH) test 
stratified by the randomization factors as entered at treatment assignment. The study hypothesis for 
the primary endpoint will be tested at a 2-sided Type 1 error rate of 0.05. 
To control the overall Type 1 error at 0.05, the primary endpoint will first be tested at a two-sided 
0.05 level.  If the primary endpoint result is significant at this level, then Holm-Bonferroni 
multiplicity testing will be conducted on the following proposed secondary endpoints applying a 
familywise two-sided alpha of 0.05:   
• 
incidence of Grade 4 OM during the Study Treatment Period;  
• 
total number of SOM days (per subject) during the OM Observation Period for the entire 
study population; and 
• 
total number of days of Grade 4 OM (per subject) during the OM Observation Period for 
the entire study population. 
Efficacy analyses will be stratified by the randomization strata: 
Cisplatin schedule (weekly vs q3weekly) 
Post-operative vs definitive treatment. 


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2. 
TABLE OF CONTENTS 
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS ...........................................................................................11 
3. 
GLOSSARY ...............................................................................................................16 
4. 
INTRODUCTION ......................................................................................................19 
4.1. 
Background .................................................................................................................19 
4.1.1. 
Oral Mucositis in Patients Treated with Chemoradiation for HNC ...........................19 
4.1.2. 
Oral Mucositis is an Unmet Medical Need.................................................................20 
4.2. 
GC4419 Overview ......................................................................................................21 
4.3. 
Study Period Definitions.............................................................................................22 
5. 
STUDY OBJECTIVES, ENDPOINTS AND PURPOSE ..........................................23 
5.1. 
Objectives ...................................................................................................................23 
5.2. 
Endpoints ....................................................................................................................24 
5.2.1. 
Rationale for Primary Endpoint ..................................................................................25 
6. 
INVESTIGATIONAL PLAN .....................................................................................26 
6.1. 
Overall Study Design ..................................................................................................26 
6.2. 
Treatment Plan and Duration of Therapy ...................................................................27 
6.2.1. 
Rationale for GC4419 Dose and Schedule Selection .................................................28 
6.2.2. 
Rationale for Cisplatin/IMRT Treatment Plan ...........................................................28 
6.2.3. 
Rationale for Tumor Follow-up and Analysis ............................................................29 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
7.1. 
Subject Inclusion Criteria ...........................................................................................29 
7.2. 
Subject Exclusion Criteria ..........................................................................................30 
7.3. 
Rationale for Patient Population .................................................................................31 
7.4. 
Screen Failures ............................................................................................................32 
7.5. 
Randomization Failures ..............................................................................................32 
7.6. 
Subject Withdrawal Criteria .......................................................................................32 
7.7. 
Study and Site Closure................................................................................................33 
8. 
GC4419/PLACEBO ...................................................................................................33 
8.1. 
Description of GC4419/Placebo .................................................................................33 
8.1.1. 
GC4419 .......................................................................................................................33 


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8.1.2. 
Placebo ........................................................................................................................34 
8.2. 
Treatment Assignment ................................................................................................34 
8.2.1. 
Blinding ......................................................................................................................34 
8.3. 
GC4419/Placebo Packaging and Labeling .................................................................34 
8.3.1. 
GC4419 .......................................................................................................................35 
8.3.2. 
Placebo ........................................................................................................................35 
8.4. 
GC4419/Placebo Storage ............................................................................................35 
8.5. 
GC4419/Placebo Preparation......................................................................................35 
8.6. 
GC4419/Placebo Administration ................................................................................36 
8.7. 
GC4419/Placebo Accountability and Compliance .....................................................39 
8.8. 
GC4419/Placebo Handling and Disposal ...................................................................39 
8.9. 
Concomitant Medications ...........................................................................................39 
8.9.1. 
Prohibited Medications ...............................................................................................40 
8.9.2. 
CYP2D6 Substrates ....................................................................................................41 
9. 
TOXICITY MANAGEMENT ....................................................................................42 
9.1. 
Dose Delays and Dose Modifications for Toxicity ....................................................42 
9.2. 
Supportive Care Guidelines ........................................................................................42 
9.2.1. 
Supportive care for chemotherapy-induced nausea and vomiting (CINV) ................43 
10. 
ASSESSMENTS.........................................................................................................43 
10.1. 
Safety Assessments .....................................................................................................43 
10.1.1. 
Clinical Assessments ..................................................................................................43 
10.1.2. 
Laboratory Assessments .............................................................................................44 
10.2. 
Oral Mucositis Assessments .......................................................................................44 
10.3. 
Radiation Therapy Quality Assurance ........................................................................45 
10.4. 
Pharmacokinetic (PK) Measurements ........................................................................45 
10.4.1. 
Pharmacokinetic (PK) Measurements of GC4419 .....................................................45 
10.5. 
Biological Surrogate Markers of Mucositis ................................................................46 
10.6. 
Tumor Status Assessment ...........................................................................................46 
10.6.1. 
Clinical Tumor Assessment ........................................................................................46 
10.6.2. 
Tumor Imaging ...........................................................................................................47 
10.6.2.1. 
Pre-Treatment Tumor Imaging ...................................................................................47 
10.6.2.2. 
Post-Treatment Tumor Imaging .................................................................................47 
10.6.3. 
Survival Status ............................................................................................................47 


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10.7. 
Schedule of Time and Events .....................................................................................47 
10.8. 
Screening ....................................................................................................................48 
10.9. 
Treatment ....................................................................................................................49 
10.9.1. 
Baseline/Day 1 (First Day of IMRT and GC4419/Placebo) .......................................49 
10.9.2. 
Day 2 of IMRT and GC4419/Placebo ........................................................................49 
10.9.3. 
Days 3 to 5 of IMRT and GC4419/Placebo ................................................................50 
10.9.4. 
Week 2 ........................................................................................................................50 
10.9.5. 
Week 3 ........................................................................................................................51 
10.9.6. 
Week 4 ........................................................................................................................51 
10.9.7. 
Week 5 ........................................................................................................................52 
10.9.8. 
Week 6 ........................................................................................................................53 
10.9.9. 
Week 7 (plus additional IMRT weeks, if needed) ......................................................53 
10.9.10. 
Last Day of IMRT or Early Termination Visit ...........................................................54 
10.10. 
Follow-up ....................................................................................................................54 
10.10.1. 
Post-IMRT OM Follow-up .........................................................................................54 
10.10.2. 
Long-term Follow-up ..................................................................................................55 
11. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................55 
11.1. 
Definitions ..................................................................................................................56 
11.1.1. 
Adverse Event (AE) ....................................................................................................56 
11.1.2. 
Serious Adverse Event (SAE) ....................................................................................56 
11.2. 
Adverse Event Reporting Requirements ....................................................................57 
11.2.1. 
Serious Adverse Events ..............................................................................................57 
11.2.2. 
All Adverse Events (AEs) Regardless of Seriousness ................................................57 
11.2.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs ....................................................................................................................57 
11.2.4. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................58 
11.2.5. 
Grading of Adverse Events .........................................................................................58 
11.3. 
Relationship to Study Drug ........................................................................................58 
11.4. 
Recording Adverse Events .........................................................................................59 
11.5. 
Follow-up of AEs and SAEs .......................................................................................60 
11.6. 
Post-Study Reporting Requirements ...........................................................................60 
11.7. 
Regulatory Reporting of Adverse Events ...................................................................61 


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11.8. 
Pregnancy ...................................................................................................................61 
11.8.1. 
Time Period for Collecting Pregnancy Information ...................................................61 
11.8.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male 
Subject ........................................................................................................................61 
12. 
STATISTICS ..............................................................................................................62 
12.1. 
General Considerations ...............................................................................................62 
12.1.1. 
Randomization and Stratification ...............................................................................62 
12.1.2. 
Treatment of Subjects Affected by Sponsor Dosing Suspension ...............................62 
12.2. 
Sample Size ................................................................................................................62 
12.3. 
Analysis Populations ..................................................................................................63 
12.4. 
Safety Analysis ...........................................................................................................63 
12.5. 
Primary Efficacy Analysis ..........................................................................................63 
12.5.1. 
Multiplicity .................................................................................................................63 
12.5.2. 
Handling of Missing Data ...........................................................................................64 
12.5.3. 
Covariate Adjustment .................................................................................................64 
12.6. 
Secondary Efficacy Analyses .....................................................................................64 
12.6.1. 
Secondary Endpoints ..................................................................................................64 
12.7. 
Exploratory Efficacy Analyses ...................................................................................64 
12.8. 
Analysis of Tumor Endpoints .....................................................................................65 
12.8.1. 
Local or Regional Progression....................................................................................65 
12.8.2. 
Distant Metastasis .......................................................................................................65 
12.8.3. 
Second Primary Neoplasm .........................................................................................65 
12.9. 
Interim Analysis ..........................................................................................................65 
13. 
ETHICS ......................................................................................................................65 
13.1. 
Ethical Conduct of the Study ......................................................................................65 
13.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval ..........................................................65 
13.3. 
Written Informed Consent ..........................................................................................66 
13.4. 
Data Monitoring Committee (DMC) ..........................................................................66 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................66 
14.1. 
Study Monitoring ........................................................................................................66 
14.2. 
Audits and Inspections ................................................................................................67 
14.3. 
Protocol Compliance ..................................................................................................67 


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14.4. 
Protocol Modifications ...............................................................................................67 
14.5. 
Information Disclosure ...............................................................................................67 
14.5.1. 
Ownership ...................................................................................................................67 
14.5.2. 
Confidentiality ............................................................................................................68 
14.5.3. 
Publication ..................................................................................................................68 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................68 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
16.1. 
Case Report Forms .....................................................................................................68 
16.2. 
Retention/Inspection of Records.................................................................................68 
17. 
LIST OF REFERENCES ............................................................................................70 
18. 
APPENDICES ............................................................................................................74 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................75 
APPENDIX 2. WORLD HEALTH ORGANIZATION (WHO) SCORE OF ORAL 
MUCOSITIS ...............................................................................................................78 
APPENDIX 3. PERFORMANCE STATUS CONVERSION ....................................................79 
APPENDIX 4. NATIONAL CANCER INSTITUTE-COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS, VERSION 5.0 ............................................80 
APPENDIX 5. RECOMMENDED REGIMENS FOR HIGH-RISK 
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV) PER 
ASCO AND MASCC GUIDELINES ........................................................................81 
APPENDIX 6. DAILY ORAL CARE RECOMMENDATIONS ..............................................83 
APPENDIX 7. CYP2D6 SUBSTRATES ...................................................................................84 
APPENDIX 8. SUMMARY OF CHANGES IN AMENDMENT 4 ..........................................85 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................16 
Table 2: 
Comparison of WHO Scale vs. NCI-CTCAE v5.0 for Oral Mucositis ......................26 
Table 3: 
Chemoradiation and GC4419/Placebo Administration Schedule  Example: 
35 Doses of GC4419/Placebo (5 days/week over 7 Week Schedule) ........................37 
Table 4: 
Pharmacokinetic Sampling Schedule to Assess GC4419 ...........................................46 
Table 5: 
Adverse Event Severity ..............................................................................................58 
Table 6: 
Schedule of Assessments ............................................................................................75 
Table 7: 
Antiemetic Dosing for Adults – High Risk (Cisplatin) ..............................................81 


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3. 
GLOSSARY 
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 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRT 
Chemo-Radiotherapy  
CS 
Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP2D6 
Cytochrome P450 Isozyme 2D6 
DDDP 
Division of Dermatology and Dental Products 
DMC 
Data Monitoring Committee 
DP 
Drug Product 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Gy 
Gray 


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Abbreviation or Specialist Term 
Definition 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HNC 
Head and Neck Cancer 
HPV 
Human Papilloma Virus 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMRT 
Intensity-Modulated Radiation Therapy 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISOO 
International Society of Oral Oncology 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IXRS 
Interactive Voice and Web Response System 
LTFU 
Long-term Follow-up 
MASCC 
Multinational Association of Supportive Care in Cancer 
M-F 
Monday to Friday 
MnSOD 
Manganese Superoxide Dismutase  
NCI 
National Cancer Institute 
NCS 
Non-Clinically Significant 
NEPA 
Netupitant and Palonosetron  
OC 
Oral Cavity 
OM 
Oral Mucositis 
OP 
Oropharynx 
OS 
Overall Survival 
PFS 
Progression Free Survival 


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Abbreviation or Specialist Term 
Definition 
PK 
Pharmacokinetic 
QOL 
Quality of Life 
REB 
Research Ethics Board 
RNA 
Ribonucleic Acid 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SCC 
Squamous Cell Carcinoma 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SOC 
Standard of Care 
SOD 
Superoxide Dismutase 
SOM 
Severe Oral Mucositis 
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 (Sonis 2009). Oral mucositis 
is readily graded using the commonly-used five-point World Health Organization (WHO) scale 
(Appendix 2). 
Most patients receiving combined chemoradiotherapy for head and neck cancer (HNC) can be 
expected to develop severe (WHO Grade 3-4) OM (Sonis, Elting et al. 2004), and nearly all 
HNC patients receiving radiation therapy (RT) with concurrent cisplatin are expected to develop 
ulcerative OM (WHO Grade 2 or higher) (Traynor, Richards et al. 2010). The consequences for 
patients developing severe OM are especially serious, because by definition, Grade 3-4 OM 
entails compromise to nutrition and/or hydration, and may require surgical procedure, RT 
interruption, and/or hospitalization. 
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 (Mendenhall, 
Amdur et al. 2006; Salama, Seiwert et al. 2007; Ang, Zhang et al. 2014; Nguyen-Tan, Zhang et 
al. 2014). The monoclonal antibody cetuximab has also been shown to increase the efficacy of 
radiotherapy for locally advanced head and neck cancer (Bonner, Harari et al. 2006). Recently 
reported results from the RTOG 1016 study in human papilloma virus (HPV)-associated 
oropharyngeal cancer showed survival after IMRT plus cetuximab to be inferior to that obtained 
with IMRT/cisplatin (Gillison, et al. 2018). 
Published observations for patients treated with RT for HNC, without additional treatment to 
prevent OM, indicate that approximately 50% of patients receiving RT alone (Bonner, Harari et 
al, 2006), and that approximately 70% of patients receiving RT plus single-agent cisplatin may 
be expected to develop severe OM, with a median duration of approximately 3-4 weeks among 
those who develop severe OM, a median time to onset of approximately 28-35 days after the 
start of therapy, and a cumulative incidence of approximately 10% per week/10 Gy. Data for the 
placebo groups in two published Phase 3 studies of Kepivance® (palifermin) in patients 
receiving RT plus single-agent cisplatin for SCCHN (Henke, Alfonsi et al. 2011; Le, Kim et al. 
2011), and results for patients receiving IMRT plus platinum plus placebo in a more recent report 
(Kudrimoti, Curtis et al. 2016) support these observations. Other observations also supporting 
these expectations come from aggregate data from approximately 380 patients in placebo groups 
who received IMRT/cisplatin for oral cavity or oropharyngeal cancers (S. Sonis, Dana Farber 
Cancer Institute, personal communication). 
Adding cetuximab to standard chemoradiation regimens for HNC increases the risk of significant 
OM (Ang, Zhang et al. 2014), 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 
(Bonner, Harari et al. 2006).  In RTOG 1016, the incidence of NCI Grade 3-4 OM was similar 
for RT plus cetuximab and RT plus cisplatin (Gillison, et al. 2018). 


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Among patients being treated for HNC, OM follows a predictable and well-documented course 
(Sonis 2011). 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 (Elting, Cooksley et al. 2007). 
OM 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 (Elting, Cooksley et al. 2007), as well as secondary infections at sites of 
ulcerative OM (Bodey, Rodriguez et al. 1978), and diminished quality of life (QOL) outcomes 
(Elting, Keefe et al. 2008). Patients with HNC may also suffer the additional complications of 
short- and long-term xerostomia, taste change, and trismus related to post-radiation fibrosis. 
These consequences are particularly pronounced in patients manifesting severe OM, and 
especially in the 20-30% who suffer Grade 4 and require artificial alimentation, usually via a 
percutaneous gastrostomy tube. 
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 (Vera-Llonch, 
Oster et al. 2006; Russo, Haddad et al. 2008). In granulocytopenic patients, mucositis is strongly 
associated with an increased risk of bacteremia and sepsis (Ruescher, Sodeifi et al. 1998). 
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 (Nonzee, Dandade et al. 2008). 
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 (Keefe 2006). Current guidelines (Lalla, 
Bowen et al. 2014) 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: 
Kepivance® (palifermin) in the setting of high-dose chemotherapy and total body irradiation, 
followed by autologous hematopoietic stem cell transplantation (HSCT), for a 
hematological malignancy. However, Kepivance® is not licensed/approved for the 
treatment of OM associated with HNC; 
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. 


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Narcotics and doxepin mouthwash are recommended or suggested by MASCC/ISOO for the 
treatment of OM-related pain. Several other agents currently used to treat OM symptoms, 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. 
Further, no approved product is available in the US (or elsewhere) for OM in the vast majority of 
these patients, especially those with solid tumors such as SCCHN. At present, palifermin is the 
only FDA-approved (licensed) product for OM but its indicated use (patients receiving HSCT for 
hematologic malignancies) is limited to a very small cohort (4%) of the total population at risk 
for OM: a cohort associated with conditioning regimens prior to stem cell transplant for the 
treatment of hematologic malignancies. The approval specifically excludes patients with solid 
tumors (Spielberger, Stiff et al. 2004). 
A few medical devices are on the market, but they generally lack sufficient data to allow 
recommendation. The mucoadhesive MuGard™ is indicated as a palliative treatment for the 
management of OM but requires administration 4 to 6 times per day for optimal effect and does 
not alter the mechanism of OM (MuGard prescribing information). 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 OM but failed to reduce the incidence of 
ulcerative or severe OM in a recently-published Phase 2 study (Rao, Trotti et al. 2014). 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. 
Therefore, current standard of care for patients with solid tumors consists of oral care protocols 
and palliative approaches to deal with painful symptoms. An urgent need remains for novel 
products, like GC4419, aimed at reducing the incidence and severity of severe OM. 
4.2. 
GC4419 Overview 
GC4419 is a novel, highly stable manganese-containing macrocyclic ligand complex with a 
molecular weight of 483 g/mol, whose activity mimics that of naturally occurring superoxide 
dismutase (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. 
GC4419 is being developed for the initial indication of reduction of the incidence and severity of 
severe OM induced by RT, with or without systemic therapy, under IND 111,539 with the 
Division of Dermatology and Dental Products (DDDP), United States FDA. 
By efficiently and rapidly removing O2•- , GC4419 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 manganese (Mn) SOD or a MnSOD transgene, exogenous Cu/Zn SOD, 
or a dismutase mimetic enantiomerically related to GC4419 (Delanian, Baillet et al. 1994; 
Epperly, Defilippi et al. 2000; Guo, Seixas-Silva et al. 2003; Murphy, Fey et al. 2008; 
Thompson, Chu et al. 2010). 


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GC4419 was studied extensively in nonclinical settings, in different animal models, and various 
human xenograft and murine syngeneic tumor models (for details see the Investigator’s 
Brochure). Nonclinical data have identified GC4419 as a promising new radioprotective, anti-
cancer and anti-inflammatory agent. 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 was studied in a Phase 1b/2a clinical study, GT-001 (NCT01921426, Anderson, Sonis, 
et al. 2018) and Phase 2b study, GT-201 (NCT02508389). In study GT-001, GC4419 was 
administered throughout the full 6- to 7-week course of chemo-radiotherapy (CRT) at doses of 
either 30 or 90 mg, Monday-Friday (M-F), and appeared to substantially reduce the duration, 
incidence, and overall severity (defined here as the incidence specifically of Grade 4) of severe 
OM compared with historical expectations (data are based on 43 evaluable subjects). Further, 
GC4419 did not appear to increase the known toxicity of the CRT regimen (IMRT plus 
concurrent cisplatin), nor did it appear to interfere with tumor response to CRT assessed through 
1 year post therapy (for details see Anderson, Sonis, et al. 2018 and the Investigator's Brochure). 
These results supported the design of the randomized, double-blind, placebo-controlled, Phase 2b 
study GT-201, with two GC4419 doses of 30 and 90 mg selected for comparison with placebo 
and administered 5 days/week. As in GT-001, patients eligible for GT-201 were required to have 
locally advanced squamous cell carcinoma of the oral cavity (OC) or oropharynx (OP), with their 
standard care calling for concurrent IMRT and cisplatin. Results from 223 randomized subjects 
indicated that GC4419 at daily dose of 90 mg resulted in statistically significant reduction on the 
primary endpoint, severe OM duration, for subjects on the 90 mg arm compared to placebo, as 
determined by the non-parametric Van Elteren test.   The median duration of SOM, as defined in 
the protocol, was 1.5 days for subjects receiving 90 mg of GC4419 vs 19 days for subjects 
receiving placebo (p=0.024).  Also, the incidence of SOM during the IMRT treatment period was 
43% for subjects receiving 90 mg of GC4419 vs 65% for subjects receiving placebo (nominal p 
value=0.009), a relative reduction of approximately 34%.  The safety profile of GC4419 in 
combination with the IMRT/platinum regimen in GT-201 study was acceptable; safety results 
with both the 90 mg dose and the 30 mg dose were similar to those with placebo.  
Additional details about the pathogenesis of OM, the mechanism of action of GC4419, and the 
results of non-clinical testing as well as the clinical trials GT-001 and GT-201 are provided in the 
Investigator's Brochure.  
4.3. 
Study Period Definitions 
Study Treatment Period: the period of time from Study Day 1 (IMRT Day 1/Baseline) through 
the last day of IMRT. Subjects who receive at least 60 Gy of IMRT will be considered to have 
completed the Study Treatment Period. 
OM (Oral Mucositis) Observation Period: the period of time from Study Day 1 (IMRT Day 
1/Baseline) through the last OM assessment. By protocol, the last OM assessment is to occur 
during the second week after completion of IMRT. 
AE (Adverse Event) Observation Period: the period of time from the date of randomization 
through 30 days post last day of cisplatin, IMRT, or GC4419/Placebo (i.e., whichever occurs 
last). 


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LTFU (Long-term Follow-up) Observation Period: the period of time from last day of IMRT 
through 24 months post-IMRT. 
5. 
STUDY OBJECTIVES, ENDPOINTS AND PURPOSE 
5.1. 
Objectives 
Primary Objective: 
To assess the effect of GC4419 administered intravenously (IV) on the incidence of severe 
oral mucositis (SOM; Grade 3-4 OM) during the Study Treatment Period in subjects 
receiving post-operative or definitive therapy with single-agent cisplatin plus Intensity-
Modulated Radiation Therapy (IMRT) for locally advanced, non-metastatic squamous 
cell carcinoma (SCC) of the oral cavity or oropharynx 
Secondary Objectives: 
To assess the effect of GC4419 administered intravenously (IV) on the incidence of Grade 4 
OM during the Study Treatment Period in subjects receiving post-operative or definitive 
therapy with single-agent cisplatin plus Intensity-Modulated Radiation Therapy (IMRT) 
for locally advanced, non-metastatic squamous cell carcinoma (SCC) of the oral cavity or 
oropharynx 
To assess the effect of GC4419 administered intravenously (IV) on the total number of days 
of Grade 3-4 OM during the OM Observation Period in subjects receiving post-operative 
or definitive therapy with single-agent cisplatin plus Intensity-Modulated Radiation 
Therapy (IMRT) for locally advanced, non-metastatic squamous cell carcinoma (SCC) of 
the oral cavity or oropharynx 
To assess the effect of GC4419 administered intravenously (IV) on the total number of days 
of Grade 4 OM during the OM Observation Period in subjects receiving post-operative or 
definitive therapy with single-agent cisplatin plus Intensity-Modulated Radiation Therapy 
(IMRT) for locally advanced, non-metastatic squamous cell carcinoma (SCC) of the oral 
cavity or oropharynx 
To confirm safety and tolerability of GC4419 administered IV in subjects receiving cisplatin 
plus IMRT for locally advanced, non-metastatic SCC of the oral cavity or oropharynx 
To evaluate potential effects of GC4419 on tumor efficacy outcomes for the study population 
Exploratory Objectives: 
To assess duration (per subject) of SOM (WHO Grade 3-4) for subjects who have 
experienced SOM during the OM Observation Period 
To assess duration of Grade 4 OM for subjects who have experienced Grade 4 OM during the 
OM Observation Period 
To assess effects of GC4419 on the cumulative incidence of SOM (WHO Grade 3-4) from 
the first IMRT fraction through the delivery of progressive, cumulative IMRT doses 
To assess effects of GC4419 on the cumulative incidence of SOM (WHO Grade 3-4) during 
the OM Observation Period 
To assess time from beginning of IMRT and IMRT dose to onset of SOM (WHO Grade 3-4) 


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To assess resolution (defined as ≤ Grade 2 OM) of SOM (WHO Grade 3-4) before the end of 
the Study Treatment Period for subjects who have experienced SOM during the Study 
Treatment Period 
To assess resolution (defined as ≤ Grade 3 OM) of Grade 4 OM before the end of the Study 
Treatment Period for subjects who have experienced Grade 4 OM during the Study 
Treatment Period 
To assess effects of GC4419 on the incidence, onset, and duration of ulcerative OM (≥ Grade 
2) 
To assess treatment delivery and delays (number and duration of delays) of IMRT and 
cisplatin 
To assess the relationship between drug exposure and safety/efficacy 
To assess the effects of GC4419 on circulating cytokine levels and gene expression levels 
To assess the effects of GC4419 on kidney function throughout the first year post-IMRT 
5.2. 
Endpoints 
Primary Endpoint: 
Cumulative incidence of SOM, defined as the proportion of subjects with any occurrence of 
WHO Grade 3-4 OM, during the Study Treatment Period 
Secondary Endpoints: 
Efficacy: 
Cumulative incidence of WHO Grade 4 OM, defined as the proportion of subjects with any 
occurrence of WHO Grade 4 OM, during the Study Treatment Period 
Total number of days (per subject) of SOM (WHO Grade 3-4) during the OM Observation 
Period for all subjects  
Total number of days (per subject) of Grade 4 OM during the OM Observation Period for all 
subjects 
Safety: 
Safety of GC4419 as measured by: 
− Frequency, duration, and severity of Adverse Events (AEs) and serious AEs 
(SAEs) during the AE Observation Period; 
− Incidence and shifts of clinically significant laboratory abnormalities 
Effect of treatment on tumor outcomes (locoregional failure, distant metastases, progression-
free survival, overall survival) during the LTFU Observation Period 
Exploratory Endpoints: 
Duration (per subject) of SOM (WHO Grade 3-4) for subjects who have experienced SOM 
during the OM Observation Period 
Duration of Grade 4 OM for subjects who have experienced Grade 4 OM during the OM 
Observation Period 


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Effects of GC4419 on the cumulative incidence of SOM (WHO Grade 3-4) from the first 
IMRT fraction through the delivery of progressive, cumulative IMRT doses 
Effects of GC4419 on the cumulative incidence of SOM (WHO Grade 3-4) during the OM 
Observation Period 
Time from beginning of IMRT and IMRT dose to onset of SOM (WHO Grade 3-4) 
Resolution (defined as ≤ Grade 2 OM) of SOM (WHO Grade 3-4) before the end of the 
Study Treatment Period for subjects who have experienced SOM during the Study 
Treatment Period 
Resolution (defined as ≤ Grade 3 OM) of Grade 4 OM before the end of the Study Treatment 
Period for subjects who have experienced Grade 4 OM during the Study Treatment 
Period 
Effects of GC4419 on the incidence, onset, and duration of ulcerative OM (≥ Grade 2) 
Treatment delivery and delays (number and duration of delays) of IMRT and cisplatin 
Relationship between drug exposure and safety/efficacy 
Effects of treatment assignment on circulating cytokine levels and gene expression levels  
Effects of treatment assignment on kidney function throughout the first year post-IMRT 
5.2.1. 
Rationale for Primary Endpoint 
The WHO scale is commonly used to assess OM in clinical care and research settings. Originally 
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 low 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 using severe OM as defined by the WHO scale as the basis for drug 
approval. Palifermin (Kepivance®) is indicated to decrease the incidence and duration of severe 
OM 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 OM in the majority of patients. Approval of palifermin was based on a reduction in 
the number of days during which patients experienced severe OM (Grade 3/4 on the WHO 
scale); other analyses included the incidence, duration, and severity of oral mucositis and the use 
of opioid analgesia (Kepivance prescribing information). Additional studies of agents to reduce 
OM—notably the 2 published studies of palifermin in the HNC population (Henke, Alfonsi et al. 
2011; Le, Kim et al. 2011) also have used the WHO scale. 


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The incidence of severe OM is planned as the single primary endpoint of this Phase 3 study. 
Secondary and exploratory endpoints are expected to provide important and clinically relevant 
data supporting the primary endpoint. 
Because of the nature of the WHO grading scale (See Appendix 2), 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. 
Many reports of OM in clinical studies use the NCI-CTCAE, in which the grading of OM is 
different from the WHO scale (Table 2). 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 2: 
Comparison of WHO Scale vs. NCI-CTCAE v5.0 for Oral Mucositis  
OM Grade 
WHO Scale 
NCI-CTCAE v5.0 
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 or ulcer that does not 
interfere 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 the current study. Separate grading of OM according to 
the NCI-CTCAE will not be performed. As in prior Galera-sponsored studies (GT-001 and GT-
201), the WHO OM score for each subject will be assessed by trained Investigator-evaluators 
followed by Quality Control process as described under GT-201 results (See Investigator’s 
Brochure). 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
GTI-4419-301 is a randomized, double-blind, placebo-controlled, multi-center international 
study conducted to evaluate GC4419 administered IV to reduce the incidence and severity of 
radiation induced OM in subjects receiving chemoradiation for SCCHN, limited to the oral 
cavity or oropharynx. 
 


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6.2. 
Treatment Plan and Duration of Therapy 
Subjects will be randomized in a 3:2 ratio to 1 of 2 arms: 
Arm A: 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 100 mg/m2 once every three weeks 
for 3 doses or 40 mg/m2 once weekly for 6-7 doses (Investigator’s choice) 
Arm B: 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 100 mg/m2 once every three weeks 
for 3 doses or 40 mg/m2 once weekly for 6-7 doses (Investigator’s choice) 
Enrollment will be stratified at randomization for 2 factors: cisplatin schedule (weekly vs 
q3week); post-operative vs definitive treatment. 
Note: Planned radiation fields in both arms must include at least 2 oral sites (left and right 
buccal mucosa, floor of mouth, left and right ventral/lateral tongue, soft palate) with each site 
receiving a cumulative dose of at least 50 Gy. 
GC4419/Placebo will be given IV by a 60-minute 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 subject’s treating physician in accordance with standard of care. Subjects 
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 any 
missed dose up 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. 
Anti-emetic prophylaxis and hematopoietic growth factor use should be administered per 
American Society of Clinical Oncology (ASCO) guidelines (Appendix 5). 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 following administration sequence should be used if 
possible: GC4419/Placebo, IMRT, prehydration, and cisplatin. Patients treated with induction 
chemotherapy prior to concomitant chemoradiation are not eligible for this study. 
All subjects will be assessed twice weekly for oral mucositis per WHO grading criteria until the 
end of the study treatment period (last day of IMRT). All subjects will continue to be assessed 
once weekly for 2 weeks after the end of the study treatment period.  
The study will be monitored by a Data Monitoring Committee (DMC). Multinational 
Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology 
(ISOO) Oral Care Education Materials and patient instructions for oral hygiene should be 


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strongly recommended.  A summary of those guidelines and instructions is appended to the 
protocol (Appendix 6). 
PK sampling to assess GC4419 will be sought from all subjects. 
6.2.1. 
Rationale for GC4419 Dose and Schedule Selection 
Data from the Phase 2 GT-201 study indicate that the acute toxicity of GC4419 and the overall 
adverse event profile in combination with IMRT/cisplatin are acceptable and as expected. Safety 
results with 90 mg dose were similar to those with Placebo and GC4419 does not appear to 
increase the toxicity of IMRT/cisplatin. In addition, the 90 mg dose of GC4419 in study GT-201 
met its primary endpoint versus Placebo in demonstrating reduced duration of severe OM, and 
with strong statistical significance (p=0.024). Also of note is that Phase 2 data have indicated an 
apparent dose response between the 90 mg, 30 mg, and Placebo arms. 
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 (Pignon, le Maitre et al. 
2009).  Further, recently reported results from the RTOG 1016 study in human papilloma virus 
(HPV)-associated oropharyngeal cancer showed survival after IMRT plus cetuximab to be 
inferior to that obtained with IMRT/cisplatin (Trotti, et al. 2018).  Accordingly, in the current 
study, the still-standard cisplatin/IMRT regimen has been chosen as it poses a significant medical 
need by virtue of the predictable and high incidence of associated severe OM. 
Standard fractionation (five fractions/week, delivered M-F) IMRT has been chosen for the 
current study. Although accelerated fractionation (six fractions/week, combined with two rather 
than three doses of cisplatin q3 weeks), has been studied, prospective lead investigators 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. Accelerated fractionation appears to increase the 
incidence of severe OM (Overgaard, Hansen et al. 2003). 
In the event that a radiation fraction is missed because of a holiday or technical issues, 
administering two fractions in a subsequent day, to maintain five fractions per week, will be 
allowed, at the discretion of the treating investigator and consistent with institutional practice. 
Cisplatin is administered concomitantly with IMRT by either a q3weekly or weekly schedule.  
Recent literature reviews (Sturtz, Wouters et al. 2017; Jacinto, Co, et al. 2017) have found no 
differences in tumor outcomes or mucositis between the two schedules.  A randomized trial in 
the adjuvant (post-operative) setting (Noronha, Joshi, et al. 2018), in which 87% of patients 
enrolled had squamous cancer of the oral cavity, cited superior progression-free survival for the 
q3weekly arm, with no difference in mucositis.  However, the weekly dose of cisplatin in that 
study was 30 mg/m2.  Other reports (Stojan, Vermorken et al. 2015; Nguyen-Tan, Zhang et al. 
2014) have described a relationship between total cisplatin dose and overall survival in 
combination with RT for HNC, with a target cumulative cisplatin dose of 200 mg/m2 or greater 
now appearing indicated as standard of care to obtain improved survival with RT/cisplatin over 
RT alone.  This threshold could be missed with weekly cisplatin doses < 40 mg/m2.  In the 
present trial, cisplatin doses of 100 mg/m2 by the q3week schedule, and 40 mg/m2 by the weekly 


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schedule, will be required.  Although the risk of severe OM may not be different according to 
cisplatin schedule, and no such difference was demonstrated in a subset analysis from GT-201 
(data not shown), stratification of randomization will be based on choice of cisplatin schedule, as 
it was in GT-201.  Either regimen will be accepted as within the IMRT/cisplatin standard of care 
for the patient population to be enrolled in the present study.   
6.2.3. 
Rationale for Tumor Follow-up and Analysis 
Although the mechanism of action, existing nonclinical data (in vitro and in vivo), and existing 
clinical data 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 GTI-4419-301 will be informed of this potential risk and the existing data as part 
of the consent process and document.  GT-001 showed no evidence of tumor protection (See 
Investigator’s Brochure). Tumor follow-up is ongoing for GT-201. 
Fakhry et al. published an analysis comparing time to and patterns of progression for HPV-
positive and HPV-negative patients treated in RTOG 0129 or RTOG 0522.  The rate of 
progression was similar in the two groups. 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 
(Fakhry et al. 2014). This information suggests that tumor control data at one year after protocol 
treatment may provide a strong indication that results are consistent with expectations.  As such, 
subjects in this Phase 3 trial will be followed for tumor progression for one year after completing 
treatment.  Subjects will continue follow-up past that point for overall survival only. 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Approximately 450 total subjects, 270 in the experimental arm (GC4419) and 180 in the control 
arm (Placebo), will be enrolled from investigational sites in the United States and Canada to 
ensure a sufficient number overall, with an assumed proportion of early discontinuations from 
OM assessments of approximately 10%. 
7.1. 
Subject Inclusion Criteria 
Patients are required to meet the following inclusion criteria before entering the study: 
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 study. 
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 of 60-72 Gy. Planned radiation 
treatment fields must include at least two oral sites (left and right buccal mucosa, floor of 
mouth, left and right ventral/lateral 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 
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3. Treatment plan to receive standard cisplatin monotherapy administered either every three 
weeks (100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 6-7 doses). The decision on 
which cisplatin regimen to use in combination with IMRT and GC4419/Placebo 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  upper-normal limit (ULN) 
− Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5  
ULN 
− Alkaline phosphatase ≤ 2.5  ULN 
8. Serum pregnancy test negative for females of childbearing potential 
9. Males and females must agree to use effective contraception starting prior to the first day 
of treatment and continuing after the last dose of GC4419/Placebo for 30 days (females) 
or 90 days (males) 
10. 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. M1 disease (distant metastasis) 
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) 
4. Prior induction chemotherapy for current HNC or any prior immunotherapy 
5. Receiving any approved or investigational anti-cancer agent other than those provided for 
in this study 
6. Concurrent participation in another interventional clinical study or use of another 
investigational agent within 30 days of first dose of GC4419/Placebo 
Note: Patients who are participating in non-interventional clinical studies (e.g., QOL, imaging, 
observational, follow-up studies, etc.) are eligible, regardless of the timing of participation. 


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7. Inability to eat soft solid food at baseline for reasons other than mouth soreness after 
surgery or dental procedures 
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 at baseline. Subjects with mouth or throat pain solely due to 
post-operative effects are eligible, however. 
12. Known history of human immunodeficiency virus (HIV) or history of 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. 
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 prior data and assumptions as described in the Investigator’s Brochure. Although some 
studies, such as the studies of palifermin for OM in patients with HNC cancer, have included 
other anatomic sites (e.g., laryngeal, hypopharyngeal), exclusion of these from the current study 
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 study, GT-001 and the 
randomized Phase 2b study, GT-201.  
Patients with unknown primary tumor whose IMRT/cisplatin treatment plans conform to study 
requirements will be eligible, provided that appropriate work up, including for tumor HPV status, 


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is consistent with an oropharyngeal or oral cavity primary site and IMRT/cisplatin treatment 
plans otherwise appropriate for the present study. 
7.4. 
Screen Failures 
A subject is considered to be a screen failure if the subject signs the informed consent form but 
withdraws consent or is deemed ineligible before being randomly assigned to a treatment arm. 
The reason why the subject was precluded from the clinical study will be collected. All subjects 
who sign the informed consent form for this study, including screening failures, will be entered 
in the IXRS. 
7.5. 
Randomization Failures 
A subject is considered to be a randomization failure if the subject 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 
information will be collected for randomization failures, as well of the reason the subject was 
precluded from the clinical study. All randomization failures will be listed on the Subject Status 
Log which is further detailed in the Regulatory Binder. Treatment assignment of randomization 
failures will remain blinded until after analysis of primary and secondary efficacy and safety 
data. 
7.6. 
Subject Withdrawal Criteria 
In accordance with the Declaration of Helsinki, a subject has the right to withdraw from the 
study at any time for any reason. The Investigator may also, at his/her discretion, discontinue a 
subject from participating in this study at any time. Additionally, study treatment may be 
discontinued for any of the following reasons: 
Adverse Event (AE) 
Medical requirement to administer a contra-indicated medication 
Subject non-compliance 
Subject has a confirmed positive serum pregnancy test 
Discontinuation of the study at the request of the Sponsor 
The primary reason for ceasing treatment with the randomized therapy (GC4419 or Placebo) will 
be clearly documented in the subject’s medical record and recorded on the appropriate CRF 
page. A subject who permanently discontinues treatment with GC4419 or Placebo will not be 
allowed to be retreated. 
If a subject discontinues randomized therapy as a result of an AE or serious adverse event (SAE), 
every attempt should be made to keep the subject in the study and continue to perform the 
required study-related follow-up and procedures. If this is not possible or acceptable to the 
subject, the subject may be withdrawn from the study. 
Subjects who withdraw consent for further administration of GC4419 or Placebo should be 
encouraged to continue and complete their standard treatment with IMRT/cisplatin, and should 
be encouraged to continue with other study procedures, notably with OM assessments as 
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If a subject withdraws consent, additional details about the reasons for that decision will be 
sought and documented. 
Withdrawn subjects will not be replaced. 
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, 
the Sponsor and the Investigator will assure that adequate consideration is given to the protection 
of the subjects’ 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 the Sponsor (as applicable) 
Resolution of all data queries 
Accountability, reconciliation, and arrangements for all unused GC4419/Placebo 
Review of site study records for completeness 
Shipment of laboratory samples (as applicable) 
In addition, the Sponsor 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 the Sponsor determines such action is 
needed, the Sponsor will discuss this with the Investigator (including the reasons for taking such 
action) at that time. When feasible, the Sponsor will provide advance notification to the 
Investigator of the impending action prior to it taking effect. 
The Sponsor 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/Research Ethics 
Board (REB) promptly and provide the reason for the suspension or termination. If the study is 
prematurely discontinued, all study data must be returned to the Sponsor. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and the Sponsor. 
8. 
GC4419/PLACEBO 
8.1. 
Description of GC4419/Placebo 
8.1.1. 
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. 


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GC4419 is formulated as a clear solution at the following concentration to support the active 
arm: 
Arm A: 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 a 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. 
8.1.2. 
Placebo 
Arm B: 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. 
8.2. 
Treatment Assignment 
Subjects will be randomly assigned to one of the two treatment arms through an interactive 
response technology (IRT). The system will assign a subject a unique randomization number that 
will remain consistent for the duration of the study. See the Pharmacy Binder for additional 
information regarding subject randomization and the IRT system. 
8.2.1. 
Blinding 
Treatment assignment should remain blinded until analyses of the primary and secondary safety 
and efficacy results of the study have been performed on the final, locked data through the end of 
post-IMRT follow-up for all subjects.  Only in the case of an emergency, when knowledge of the 
investigational product is essential for the clinical management or welfare of the subject, may the 
Investigator unblind an individual subject’s treatment assignment prior to the completion of the 
primary and secondary safety and efficacy analyses. The Investigator will, whenever possible, 
discuss options with the Medical Monitor or appropriate Sponsor/CRO study personnel before 
unblinding. If the blind is broken for any reason and the Investigator is unable to contact the 
Sponsor prior to unblinding, the Investigator must notify the Sponsor/CRO as soon as possible 
following the unblinding incident without revealing the subject’s study treatment assignment, 
unless the information is important to the safety of subjects remaining in the study.  
If a serious adverse event (SAE; as defined in Section 11.1.2) is reported to the Sponsor/CRO, 
the Sponsor/CRO staff may unblind the treatment assignment for the individual subject. If an 
expedited regulatory report to one or more regulatory agencies is required, the report will 
identify the subject’s treatment assignment, consistent with applicable regulations for the 
territory in which the report is made. When applicable, a copy of the regulatory report may be 
sent to investigators in accordance with relevant regulations, the Sponsor policy, or both. 
8.3. 
GC4419/Placebo Packaging and Labeling 
GC4419 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, 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 or Placebo. 


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8.3.1. 
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. Further label details will be 
provided in a separate Pharmacy Manual. 
8.3.2. 
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. Further label details will be 
provided in a separate Pharmacy Manual. 
8.4. 
GC4419/Placebo Storage 
GC4419/Placebo must be stored at 2°C to 8°C at all times until use.  Study drug must not be 
frozen at any time. Temperature excursions up to 25°C or down to 0.1°C for four hours are 
accepted; however, the Sponsor or its designee must be notified immediately of the temperature 
excursion to ensure proper oversight. 
Once prepared, the IV bags containing GC4419/Placebo saline mixtures must be administered to 
subjects within 24 hours. GC4419/Placebo saline mixtures should spend as little time as possible 
outside refrigerated conditions, not exceeding more than 6 hours at ambient temperature, and 
must never be frozen. If freezing of the material is evident, that supply must be quarantined per 
institutional guidelines and the Sponsor or its designee must be notified immediately. 
8.5. 
GC4419/Placebo Preparation 
GC4419/Placebo 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 3:2 with respect to treatment arms A and B. 
GC4419 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 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 for a total volume of 
260 mL). No additional modifications or adjustments are to be made to the infusion solution. 
The GC4419 solution may appear clear or have a slight yellowish tint. Although solutions should 
be free of particulates, it is possible that some vials may have some fine visible particulates. 
Infusions must be prepared using a sterile 0.2 or 0.22 micron syringe filter prior to introduction 
into the infusion bag or a sterile 0.2 or 0.22 micron inline filter must be used during IV 
administration. Filtration does not influence dosage calculations. 
NOTE:  Filtration is mandatory, either during preparation with syringe filters or at IV 
administration with inline filters. Unfiltered GC4419 solution or infusion solution must not 
be administered to patients.  
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Note: Investigational staff who prepare infusion solutions cannot be oral evaluators. Any 
investigational staff that prepare infusions should maintain a strict blind of treatment 
assignment. In the event a vial contains particulates or is discolored with a slight yellowish tint 
that could indicate active drug, such an unblinded observation should not be discussed with 
internal site staff including those that may be directly involved in subject assessments. 
8.6. 
GC4419/Placebo Administration 
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. If sterile 0.2 or 
0.22 micron syringe filters are not used during infusion preparation, 0.2 or 0.22 micron inline 
filters must be used during IV administration. 
To facilitate administration of GC4419/Placebo according to the study schedule, an indwelling 
venous access device may be used, at the discretion of the treating Investigator. 
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 3 outlines the chemoradiation and GC4419/Placebo administration schedules. Please note 
chemotherapy is not required to be administered on the study days listed in Table 3 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 subject’s treating physician in accordance with standard of care. Subjects 
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.


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Table 3: 
Chemoradiation and GC4419/Placebo Administration Schedule  
Example: 35 Doses of GC4419/Placebo (5 days/week over 7 Week Schedule) 
Treatment 
Week 1 
Week 2 
Week 3 
Week 4 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
GC4419/Placebo1 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cisplatin2 
Tri-Weekly 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Weekly 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Radiation3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment 
Week 5 
Week 6 
Week 7 
Day 
29 
Day 
30 
Day 
31 
Day 
32 
Day 
33 
Day 
36 
Day 
37 
Day 
38 
Day 
39 
Day 
40 
Day 
43 
Day 
44 
Day 
45 
Day 
46 
Day 
47 
GC4419/Placebo1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cisplatin2 
Tri-Weekly 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Weekly 
X 
 
 
 
 
X 
 
 
 
 
X4 
 
 
 
 
Radiation3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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. Subjects should resume 
GC4419/Placebo administration when IMRT resumes. If a subject 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 (100 mg/m2) or weekly regimen (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. 


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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 of 60-72 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 cumulative Gy. 
4 The 7th dose of cisplatin will only be administered if the subject is on the 7-dose weekly cisplatin schedule (weekly cisplatin schedule may be 6 or 7 doses, 
depending on Investigator choice). 


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8.7. 
GC4419/Placebo Accountability and Compliance 
Compliance with GC4419/Placebo dosing, including administration details (e.g., volume, start, 
stop times, etc.) should be documented in the source documents and recorded on the CRF. 
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), subject dispensing records, and quantity of 
GC4419/Placebo returned or destroyed. Dispensing records will document quantities received 
from the Sponsor and quantities dispensed to subjects, including container number or lot number, 
date dispensed, subject identifier number, subject 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 the Sponsor, together with drug 
accountability records, will be retained according to the regulations governing record retention. 
The Investigator will not allow GC4419/Placebo to be given to any patient not included in the 
study or to any unauthorized person. 
8.8. 
GC4419/Placebo Handling and Disposal 
After completion of the study, all unused GC4419/Placebo will be inventoried and, if possible, 
destroyed locally at the site. GC4419/Placebo should not be returned directly to the Sponsor 
unless specifically requested by the Sponsor. 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. 
8.9. 
Concomitant Medications 
All concomitant therapies (i.e., prescription and over-the-counter medications) taken by subjects 
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. 
Anti-emetic prophylaxis and hematopoietic growth factors should be used per ASCO guidelines 
(Hesketh, Kris et al. 2017). 
Subjects who withdraw consent for GC4419/Placebo should be encouraged to continue and 
complete standard IMRT/cisplatin treatment and other protocol procedures, notably scheduled 
OM assessments. 
However, if a subject withdraws consent for the study or is removed from the study completely 
(i.e., the subject is no longer participating in any study procedures or follow-up) no further data 
should be collected after the date of the subject’s study discontinuation.   


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8.9.1. 
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®, Pharixia®, Tantum Verde) 
Cetuximab (Erbitux®) 
Glutamine in any form 
GM-CSF applied topically 
‘Magic mouthwashes’ or ‘Miracle mouthwashes’ are permitted, provided they do not 
contain: 
− Chlorhexidine 
− Hydrogen peroxide 
− Diphenhydramine (Benadryl®) liquid formulation 
− Tetracycline 
− Any other listed disallowed medications 
− Notes: 
o Topical lidocaine preparations are permitted 
o Diphenhydramine (Benadryl®) administered as tablets or by injection is 
permitted 
MuGard™, Gelclair®, Episil®, or other barrier devices 
Caphosol® 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildenafil, tadalafil, or similar 
agents) or other drugs that in the judgment of the treating Investigator could create a risk 
of a precipitous decrease in blood pressure are prohibited 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 
are prohibited until at least 24 hours after the last dose of GC4419 
Palifermin (Kepivance®) or other keratinocyte or fibroblast growth factor 
Povidone-iodine rinses 
Steroid rinses 
Sucralfate in suspension form (use of sucralfate tablets is permitted) 


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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 or perceived herbal/homeopathic or other remedies for OM, 
which are considered investigational for purposes of this study (includes nitric oxide) 
All medication restrictions begin on Day 1 of IMRT and GC4419/Placebo. All medication 
restrictions end after post-IMRT OM follow-up is completed unless otherwise noted. 
Subjects 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. 
Although unlikely to affect OM, diphenhydramine (Benadryl®) should not be used in 
mouthwashes or rinses. 
Chlorhexidine oral rinse may exacerbate OM and should not be used. 
Mouthwashes or rinses containing sodium bicarbonate, clotrimazole (Mycelex), nystatin, 
fluconazole (Diflucan), viscous xylocaine, and/or viscous lidocaine are permitted. If a subject 
uses “Magic Mouthwashes” or “Miracle Mouthwashes,” all ingredients must be recorded in the 
subject’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. 
Oral care per International Society of Oral Oncology (ISOO) guidelines is strongly 
recommended for all subjects as part of standard of care (Appendix 6). 
8.9.2. 
CYP2D6 Substrates 
In vitro, GC4419 inhibited cytochrome P450 isozyme 2D6 (CYP2D6) with an IC50 of 0.079 
µM. Other cytochrome P450 isozymes were not inhibited in vitro. This prompted a clinical drug-
drug interaction study in healthy human subjects, which demonstrated that GC4419 is a strong 
inhibitor of CYP2D6.    
Concomitant use of GC4419 increases the concentration of drugs that are CYP2D6 substrates, 
which may increase the risk of toxicities of these drugs. Concomitant use of GC4419 with 
CYP2D6 substrates with a narrow therapeutic range should be considered carefully (CYP2D6 
substrates where minimal increases in concentration of the substrate may lead to serious or life-
threatening toxicities). Such CYP2D6 substrates include certain beta blockers (e.g., propranolol 
and metoprolol), antidepressants (e.g., tricyclics), antipsychotics (e.g., phenothiazines and most 
atypicals), and antiarrhythmics (e.g., propafenone, flecainide) (see Appendix 7 for additional 
examples). 


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In addition, concomitant use of GC4419 may decrease the concentration of active metabolites of 
prodrugs that require CYP2D6 for activation. Concomitant use of GC4419 with CYP2D6 
prodrug substrates requiring functional CYP2D6 activity for their clinical benefit (e.g., codeine, 
tramadol, taxomifen) may decrease their effectiveness. 
Concomitant administration of a CYP2D6-substrate drug concurrent with administration of 
GC4419 should be limited to cases in which the treating investigator has determined that the use 
of the specific CYP2D6-substrate drug is medically necessary. In such cases, the patient should 
be carefully observed for clinical adverse events of the CYP2D6-substrate drug, the dose of 
which may require reduction. 
9. 
TOXICITY MANAGEMENT 
9.1. 
Dose Delays and Dose Modifications for Toxicity 
The following toxicity requires a 25% dose reduction in GC4419/Placebo: 
Grade 2 or greater hypotension within 2 hours after the start of GC4419/Placebo infusion 
(i.e., anytime from start of infusion through 1 hour after end of infusion). 
The dose of GC4419 or Placebo may be reduced by 25% for Grade 3-4 adverse events (AEs) 
judged by the Investigator to be likely attributable to the study infusion. 
Two dose reductions for toxicity will be permitted per subject. After the first event, the subject 
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 subject will be re-challenged at 50% of the original dose 
(5.0 mL GC4419/Placebo in 250 mL normal saline). Subjects who are unable to tolerate 
GC4419/Placebo infusions following 2 dose reductions must be discontinued from the study 
treatment but should continue with cisplatin/IMRT and other study assessments and procedures, 
with the concurrence of the treating Investigator, if the subject maintains informed consent to do 
so. 
For other toxicities (including those attributable to cisplatin and IMRT), management will be per 
institutional and ASCO guidelines and Investigator judgment. 
The Sponsor strongly recommends managing treatment modifications for cisplatin related 
toxicities 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.  
OM will not be considered an AE requiring dose modification for the purposes of this study. 
9.2. 
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 8.9.1. 


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9.2.1. 
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 5). Adult patients who are treated 
with cisplatin (considered a high-emetic-risk single agent for the purposes of these guidelines) 
should be offered a four-drug combination of a NK1 receptor antagonist, a serotonin (5-HT3) 
receptor antagonist, dexamethasone, and olanzapine. Dexamethasone and olanzapine should be 
continued on days 2 to 4. (Type: evidence based, benefits outweigh harms; quality of evidence: 
high; strength of recommendation: strong.) (Hesketh, Kris et al. 2017). 
Supportive care for CINV should be optimized, per ASCO and MASCC guidelines, before 
GC4419 dose is reduced for nausea and vomiting. 
10. 
ASSESSMENTS 
The study procedures to be conducted for each subject enrolled in the study are described in the 
text that follows and presented in the Schedule of Assessments in Appendix 1. 
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 deviations potentially 
affecting subject safety, GC4419/Placebo administration or the assessment of safety, efficacy 
and tolerability parameters. 
10.1. 
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. 
10.1.1. 
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 Appendix 3 for conversion criteria for Karnofsky to ECOG) 
Vital signs are required to be taken at Screening, Day 1 (Baseline), once during Week 4, once 
during Week 7 and any additional IMRT weeks, and on the Last Day of IMRT. On Day 1 
(Baseline) and Day 22, blood pressure must be measured at the following times: 
1. Within 30 minutes prior to the pre-GC4419/Placebo PK draw, and  
2. After GC4419/Placebo infusion, prior to standing and prior to the End of 
GC4419/Placebo Infusion PK draw. 


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10.1.2. 
Laboratory Assessments 
All protocol required clinical laboratory assessments from screening through end of treatment 
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 11.2. 
The following laboratory assessments are defined when referenced in the schedule of events 
(Table 6) 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, blood urea nitrogen (BUN), creatinine, sodium, 
potassium, calcium, albumin, total protein, direct bilirubin, total bilirubin, alkaline 
phosphatase, ALT (SGPT), AST (SGOT), chloride, phosphate, bicarbonate, magnesium. 
Serum Cotinine Test: required for all subjects at Baseline, Week 4, and Last Day of IMRT. 
Serum Pregnancy Test: required for all females of childbearing potential. Lack of 
childbearing potential must be noted in the source documents, if applicable. 
Blood urea nitrogen (BUN) and creatinine measurements will also be taken at 3, 6, 9, and 12-
months post-IMRT to assess kidney function. These assessments will be done at local labs. 
10.2. 
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 two days apart) within each five-day IMRT 
treatment period. The extent of subjects’ OM will be assessed by a trained evaluator and scored 
using the WHO OM toxicity grading scale. All subjects must have an oral assessment on the last 
day of IMRT treatment. If a subject withdraws for any reason prior to the end of IMRT, a 
complete oral assessment should be done on that day. 
All subjects will be evaluated at 7 ± 2 calendar days from the last day of IMRT (Post-IMRT 
Week 1) and 14 ± 2 calendar days from the last day of IMRT (Post-IMRT Week 2).  
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 subject. 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 
subject’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: 


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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 Appendix 2. 
10.3. 
Radiation Therapy Quality Assurance 
Quality assurance for IMRT will be conducted by a prospective review of the overall treatment 
plan, at the time of subject screening, by a radiation oncologist who is not an Investigator on the 
study. In addition to IMRT treatment, dosimetry and dose volume histograms will be collected 
after simulation. The 50-Gy isodose line should be clearly indicated, along with relevant imaging 
through the anatomic region for planned treatment.  Confirmation of appropriate planned doses 
to oral cavity and oropharynx sub-sites for eligibility will be confirmed. 
This information will be available for summary and retrospective analysis at the end of the study. 
10.4. 
Pharmacokinetic (PK) Measurements 
10.4.1. 
Pharmacokinetic (PK) Measurements of GC4419 
PK sampling will be sought from all subjects for GC4419. 
Plasma samples for GC4419 PK measurements will be collected in two cycles: Study Days 1 and 
2, and on Study Day 22. On Study Days 1 and 22, four samples will be drawn as follows: 
The first sample will be drawn prior to GC4419/Placebo administration. 
The second sample will be drawn within 10 minutes after the end of GC4419/Placebo infusion. 
The third sample will be drawn within 10 minutes after the end of IMRT. 
The fourth and final sample will be drawn between 60 and 180 minutes after the end of 
GC4419/Placebo infusion. 
On Study Day 2 only one PK sample will be drawn. This sample should be drawn prior to the 
GC4419/Placebo infusion on Day 2. 
Table 4 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 discussed with the Sponsor or its representative ahead of time. 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. 
 


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Table 4: 
Pharmacokinetic Sampling Schedule to Assess GC4419 
Timepoint 
Day 1 
Day 2 
Day 22 
Pre-GC4419/Placebo 
X 
X 
X 
End of GC4419/Placebo Infusion (+10min) 
X 
 
X 
Post-IMRT (+10min)  
X 
 
X 
60-180 min Post End of GC4419/Placebo Infusion 
X 
 
X 
10.5. 
Biological Surrogate Markers of Mucositis 
Biological surrogate markers of mucositis will be assessed in all subjects 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 subjects during the treatment phase of the 
study. Refer to Schedule of Assessments in Appendix 1, Table 6 for the schedule of biomarker 
assessments for each treatment schedule. For subjects 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. 
Blood draws for cytokine analysis should be conducted on an OM assessment day. For 
standardization, the Sponsor recommends conducting the cytokine draw on the day of the second 
OM assessment. 
10.6. 
Tumor Status Assessment 
10.6.1. 
Clinical Tumor Assessment 
The subject’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) 
The following tumor status information will be collected at each of the above time points: 
Disease progression – locoregional and distant metastasis 
Development of second primary tumors 
Additional malignancies  
A head/neck/oral exam to assess the tumor status is sufficient on the Last day of IMRT if disease 
progression is not suspected. If disease progression is suspected, a laryngopharyngoscopy should 
be conducted on the Last day of IMRT.  
At Months 3, 6, 9, and 12 post-IMRT, a brief history & a physical examination by a Radiation 
Oncologist, Medical Oncologist, ENT, or Head & Neck Surgeon, including a 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure), must be conducted. If 
local/regional progression or recurrence has already been discovered at a previous visit, a 
laryngopharyngoscopy is no longer required at future visits. However, if distant progression is 


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discovered at a previous visit, a laryngopharyngoscopy is still required at subsequent visits to 
assess the subject for local/regional progression/recurrence. A head/neck/oral exam must always 
be conducted at months 3, 6, 9, and 12 post-IMRT. 
10.6.2. 
Tumor Imaging 
10.6.2.1. Pre-Treatment Tumor Imaging 
Radiographic tumor imaging must occur within 60 days prior to the first day of IMRT (Baseline) 
for definitively treated subjects. Pre-surgical imaging should be used if available for post-
operatively treated subjects, even if the imaging occurs prior to the 60-day window. If pre-
surgical imaging was not done, post-surgical imaging can be used. 
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 subject has no evidence of disease at Baseline, it should be clearly indicated. 
10.6.2.2. Post-Treatment Tumor Imaging 
Radiographic imaging must be performed at Month 12 post-IMRT for all subjects. Subjects 
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.  
10.6.3. 
Survival Status 
Subjects will be followed for survival for two years after 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) 
10.7. 
Schedule of Time and Events 
A schedule of study assessments table is located in Appendix 1, Table 6. Minor changes to the 
assessment schedule may be made to accommodate holidays, administrative closures, etc., which 
if necessary, are not considered deviations by the Sponsor. Sites should contact the Sponsor (or 
its representative) prospectively to address rescheduling protocol assessments and data handling. 


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10.8. 
Screening 
The following screening observations and procedures will be completed within 28 days of IMRT 
and GC4419/Placebo start: 
Obtain a signed IRB/IEC/REB-approved informed consent form (ICF) 
Confirm subject eligibility by reviewing inclusion/exclusion criteria 
Obtain medical history, tobacco use history, and alcohol use history 
Obtain HNC history; HNC history should include: 
− Tumor HPV status, and strain(s) if known 
− Pre-treatment tumor imaging (See Section 10.6.2.1) 
− Prior treatments 
− Confirmation of histopathological diagnosis of SCC 
− Tumor staging (AJCC 8th Edition) (pre-surgical staging for surgical subjects if 
available; otherwise, provide post-surgical staging) 
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 subjects, the subject 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 AEs from date of randomization 
Record/update medical conditions and illnesses that have occurred since the subject signed 
the ICF and record in medical history 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
− Biomarker sample for pro-inflammatory cytokine analysis (See Section 10.5) 
− For subjects who consent separately: RNA sample (PAXgene) for genomic 
studies (See Section 10.5) 
− Serum pregnancy test for women of childbearing potential 


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All questions related to subject eligibility should be directed to Galera’s Medical Monitor or 
designee. 
10.9. 
Treatment 
10.9.1. 
Baseline/Day 1 (First Day of IMRT and GC4419/Placebo) 
Prior to receiving the first dose of GC4419/Placebo the following observations and procedures 
will be conducted for all subjects: 
Confirm continued subject eligibility by reviewing inclusion/exclusion criteria 
Measure vital signs, body weight, and ECOG Performance Status 
Blood pressure must be measured within 30 minutes prior to pre-GC4419/Placebo Infusion 
PK blood draw (See Section 10.1.1) 
Record BSA (used to confirm cisplatin dosing) 
Ensure concomitant medications have been recorded from date of randomization 
Ensure AEs have been recorded from date of randomization 
Record/update medical conditions and illnesses that have occurred since the subject signed 
the ICF and record in medical history.  
Record tobacco use 
Conduct first OM assessment for the week and record the severity using the WHO score 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
− Cotinine test 
− PK sampling (See Section 10.4) 
− Biomarker sample for pro-inflammatory cytokine analysis (See Section 10.5) 
Administer the first GC4419/Placebo dose by continuous intravenous infusion over 60 minutes.  
Following GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects: 
Measure blood pressure prior to End of GC4419/Placebo Infusion PK draw (See Section 
10.1.1) 
Draw blood for PK sampling (See Section 10.4) 
Administer IMRT as soon as possible but no later than 60 minutes following the end of 
GC4419/Placebo dosing.  
10.9.2. 
Day 2 of IMRT and GC4419/Placebo 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects: 


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Record changes to concomitant medications 
Record AEs 
PK sampling (Section 10.4) 
Administer the second GC4419/Placebo dose by continuous intravenous infusion. IMRT must 
begin as soon as possible but no later than 60 minutes following the end of GC4419/Placebo 
dosing. 
10.9.3. 
Days 3 to 5 of IMRT and GC4419/Placebo 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on Days 3, 4, and 5 unless otherwise noted: 
Record changes to concomitant medications 
Record AEs 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on Day 3, 4, or 5 unless otherwise noted: 
Conduct second OM assessment for the week and record the severity using the WHO score 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
Administer GC4419/Placebo dose by continuous intravenous infusion. IMRT must begin as soon 
as possible but no later than 60 minutes following the end of GC4419/Placebo dosing. 
10.9.4. 
Week 2 
Prior to GC4419 administration the following observations and procedures will be conducted for 
all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to GC4419/Placebo administration the following procedure will be conducted for all 
subjects twice during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects once this week: 
For subjects receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
Measure body weight 
Record tobacco use 
Draw blood for laboratory measurements 
− Chemistry profile 


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− Hematology profile 
− Biomarker sample for pro-inflammatory cytokine analysis (See Section 10.5) 
Administer GC4419/Placebo dose by continuous intravenous infusion. IMRT must begin as soon 
as possible but no later than 60 minutes following the end of GC4419 dosing. 
10.9.5. 
Week 3 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to GC4419/Placebo administration the following procedure will be conducted for all 
subjects twice during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects once this week: 
For subjects receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
Measure body weight 
Record tobacco use 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
Administer GC4419/Placebo doses by continuous intravenous infusion. IMRT must begin as 
soon as possible but no later than 60 minutes following the end of GC4419 dosing. 
10.9.6. 
Week 4 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to IMRT administration the following procedure will be conducted for all subjects twice 
during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects once this week: 
Perform symptom-directed PE 
Measure vital signs, body weight, and ECOG Performance Status 


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Record BSA (used to confirm chemotherapy dosing) 
Record tobacco use 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile  
− Cotinine test 
− Biomarker sample for pro-inflammatory cytokine analysis (See Section 10.5) 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on Day 22 only: 
Draw blood for PK sampling (See Section 10.4) 
Measure blood pressure within 30 minutes prior to pre-GC4419/Placebo Infusion PK blood 
draw (See Section 10.1.1) 
Administer GC4419/Placebo doses by continuous intravenous infusion.  
Following GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on Day 22 only: 
Measure blood pressure (See Section 10.1.1) 
Draw blood for PK sampling (See Section 10.4) 
IMRT must begin as soon as possible but no later than 60 minutes following the end of GC4419 
dosing. 
10.9.7. 
Week 5 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to GC4419/Placebo administration the following procedure will be conducted for all 
subjects twice during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects once this week: 
For subjects receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
Measure body weight 
Record tobacco use 
Draw blood for laboratory measurements 
− Chemistry profile 


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− Hematology profile 
Administer GC4419/Placebo doses by continuous intravenous infusion. IMRT must begin as 
soon as possible but no later than 60 minutes following the end of GC4419 dosing. 
10.9.8. 
Week 6 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to IMRT administration the following procedure will be conducted for all subjects twice 
during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to IMRT administration the following observations and procedures will be conducted for 
all subjects on the once this week: 
For subjects receiving weekly cisplatin, record BSA (used to confirm cisplatin dosing) 
Measure body weight 
Record tobacco use 
Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
− Biomarker sample for pro-inflammatory cytokine analysis (See Section 10.5) 
Administer GC4419/Placebo doses by continuous intravenous infusion. IMRT must begin as 
soon as possible but no later than 60 minutes following the end of GC4419 dosing. 
10.9.9. 
Week 7 (plus additional IMRT weeks, if needed) 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on all IMRT days: 
Record changes to concomitant medications 
Record AEs 
Prior to IMRT administration the following procedure will be conducted for all subjects twice 
during this week, at least two days apart: 
Conduct OM assessment and record the severity using the WHO score 
Prior to IMRT administration the following observations and procedures will be conducted for 
all subjects once this week: 
Record tobacco use 
Measure vital signs, body weight, and ECOG Performance Status 


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Draw blood for laboratory measurements 
− Chemistry profile 
− Hematology profile 
If receiving cisplatin this week, record BSA (used to confirm cisplatin dosing) 
Note: It is recommended that these assessments be completed on the last day of IMRT to 
avoid having to duplicate them. 
Administer GC4419/Placebo doses by continuous intravenous infusion. IMRT must begin as 
soon as possible but no later than 60 minutes following the end of GC4419 dosing. 
10.9.10. 
Last Day of IMRT or Early Termination Visit 
Prior to GC4419/Placebo administration the following observations and procedures will be 
conducted for all subjects on the last day of IMRT or if the subject terminates study participation 
early: 
Conduct a complete physical examination 
Measure vital signs, body weight, and ECOG status 
Conduct clinical tumor assessment 
Conduct OM assessment and record the severity using the WHO score 
Record any changes to concomitant medications 
Record AEs 
Draw blood for laboratory measurements 
− Chemistry profile 
− 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 safety tests (chemistry and hematology 
profiles) do not need to be conducted again 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. 
− Cotinine test 
− Biomarker sample for pro-inflammatory cytokine analysis (see Section 10.5) 
− For subjects who consent separately: RNA sample (PAXgene) for genomic 
studies (see Section 10.5) 
10.10. 
Follow-up 
10.10.1. 
Post-IMRT OM Follow-up 
All subjects will be evaluated at 7 ± 2 calendar days from the last day of IMRT (Post-IMRT 
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At each visit, the following should be completed: 
Conduct OM assessment and record the severity using the WHO score 
Record AEs and changes to concomitant medications through 30 days following the last dose 
of IMRT, cisplatin, or GC4419/Placebo (i.e., whichever occurs last). 
10.10.2. 
Long-term Follow-up  
All subjects will be followed for one year post-IMRT for tumor recurrence/progression.    
Subjects will be seen every 3 months (Months 3, 6, 9, and 12 post-IMRT) ± 30 days for each 
visit. At each of these visits the subject should be seen by a Radiation Oncologist, Medical 
Oncologist, ENT, or Head & Neck Surgeon and the following assessment should be conducted: 
Clinical tumor assessment (See Section 10.6.1) 
 
Note: a laryngopharyngoscopy is required at Months 3, 6, 9, and 12 post-IMRT. 
However, if local/regional progression or recurrence has already been discovered at a 
previous visit, a laryngopharyngoscopy is no longer required at future visits. If distant 
progression is discovered at a previous visit, a laryngopharyngoscopy is still required at 
subsequent visits to assess the subject for local/regional progression/recurrence. A 
head/neck/oral exam must always be conducted at Months 3, 6, 9, and 12 post-IMRT. 
Survival status assessment (See Section 10.6.3) 
Radiographic imaging must be performed at Month 12 post-IMRT for all subjects. Subjects 
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 10.6.2.2, 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. 
The following assessments must also be conducted at 3, 6, 9, and 12 months post-IMRT: 
BUN and creatinine assessment 
Weight assessment 
Subjects will continue to be followed for survival only for two years post-IMRT at 16, 20 and 24 
months (see section 10.6.3). 
11. 
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 
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11.1. 
Definitions 
The following definitions of terms are guided by the ICH and the US CFR and are included here 
verbatim. 
11.1.1. 
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. 
11.1.2. 
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] 
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 
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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. 
11.2. 
Adverse Event Reporting Requirements 
11.2.1. 
Serious Adverse Events 
All events meeting the criteria for Serious Adverse Events (see Section 11.1.2) 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. 
11.2.2. 
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 subject’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 subject’s source documents and on the CRF 
regardless of frequency, severity (grade) or assessed relationship to randomized therapy. 
11.2.3. 
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 
expected for the subject’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 
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Grade 3 or Grade 4 per NCI CTCAE v5.0 
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 11.1. 
11.2.4. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Oral mucositis will not be reported as an AE as it is captured as a study endpoint in the CRF. 
Progressive disease found by scan or on clinical evaluation should be captured on the applicable 
CRF pages and not as an AE. 
11.2.5. 
Grading of Adverse Events 
The severity of adverse events will be designated as mild, moderate, severe, life threatening, or 
fatal per NCI CTCAE version 5.0. If not specifically addressed in NCI CTCAE version 5.0, use 
Table 5 below: 
Table 5: 
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. 
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. 
11.3. 
Relationship to Study Drug 
All AEs will be categorized by the Investigator with respect to their relationship to 
GC4419/Placebo. The Investigator should consult the IB and/or product information in the 
determination of his/her assessment. The relationship between GC4419/Placebo and the AE may 


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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 subject’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 subject’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 subject’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. 
11.4. 
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 11.2. 
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 
Subject verbal reports to the investigational staff and documented in the medical chart 
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) 


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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 11.3 
Management of GC4419/Placebo administration and other action taken to alleviate the 
clinical events 
Clinical outcome of the AE 
11.5. 
Follow-up of AEs and SAEs 
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. 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject 
and provide further information on the subject’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 within 30 days after last dose of GC4419/Placebo 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. 
Routine collection of AEs will stop 30 days after last dose of GC4419/Placebo, IMRT, or 
cisplatin (i.e., whichever occurs last); however, collection of clinical data will continue on AEs 
of interest or as clinical circumstances warrant that exceed the 30 days after last dose of 
GC4419/Placebo, per below and described in other sections of the Protocol: 
• OM: 2 weeks post last IMRT dose (Section 10.10.1) 
• 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 11.6 and 11.8). 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 the Sponsor, 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 subject dies during participation in the study or during a 
recognized follow-up period, the Sponsor will be provided with a copy of any post-mortem 
findings, including histopathology. 
11.6. 
Post-Study Reporting Requirements 
Although such information may not be routinely sought or collected by the Sponsor, SAEs that 
occur after the subject has completed a clinical study may be reported. Such cases will be 
evaluated for expedited reporting. 


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11.7. 
Regulatory Reporting of Adverse Events 
The Sponsor will have final determination of when an event must be reported to the relevant 
regulatory authorities and is responsible for notifying the relevant regulatory authorities of 
certain events. The Investigator will report all 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 study. 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 the Sponsor including documentation that the IRB/IEC/REB 
was notified of each safety report. 
11.8. 
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 (females) or 90 days 
(males) following the last dose of GC4419/Placebo. 
11.8.1. 
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 subject’s pregnancy. The subject will be followed throughout 
the course of the pregnancy. Generally, follow-up will be no longer than 6 to 8 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. 
11.8.2. 
Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Subject 
The Investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while the male partner is participating in this study. The 
Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor 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 be forwarded to the Sponsor. Generally, follow-up will be no longer than 6 to 8 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. 


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12. 
STATISTICS 
12.1. 
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. 
12.1.1. 
Randomization and Stratification 
Eligible subjects will be randomized 3:2 to the two treatment arms. Randomization will be 
stratified by: 
Assigned cisplatin schedule (q3 weeks or weekly).  
Post-operative vs. definitive treatment 
12.1.2. 
Treatment of Subjects Affected by Sponsor Dosing Suspension 
On April 28, 2019, the Sponsor voluntarily suspended dosing in the trial following observation 
of fine particulate matter in two lots of clinical Drug Product (DP) at the 9-month stability test 
point.  Subsequent analysis found that these two DP lots remained within specifications, and the 
adverse event profile in subjects who had received GC4419 from them was not different from 
observations in subjects who had received GC4419 from unaffected DP lots. Particulates had 
neither been observed in the DP lots in question at prior test points (3 and 6 months), nor in prior 
DP lots. The FDA’s Division of Dermatology and Dental Products subsequently placed the IND 
on full clinical hold on July 15, 2019. The Sponsor submitted a Complete Response to Clinical 
Hold on August 7, 2019, and FDA removed the clinical hold on August 30, 2019. No subjects 
were enrolled to the study or received study drug from April 28, 2019 until after the removal of 
the clinical hold. 
The “intent to treat” (ITT) population is defined to consist of all randomized subjects who 
receive at least one dose of blinded GC4419 or placebo. However, when the Sponsor suspended 
dosing, 28 subjects were in the course of receiving GC4419 or placebo. These 28 subjects will be 
excluded from the ITT analysis on the ground that their participation does not reflect an adequate 
test of the hypothesized effects of the experimental agent. 
12.2. 
Sample Size 
Approximately 450 total subjects (270 GC4419:180 Placebo) will be enrolled from 
investigational sites in the United States and Canada to obtain approximately 400 ITT subjects 
(240 GC4419:160 Placebo). The proposed ITT sample size of 400 assumes that 10% will 
discontinue early, yielding approximately 216 subjects in the experimental arm and 
approximately 144 in the Placebo arm who will complete their IMRT course. 
With 144 subjects in the control arm and 216 subjects in the experimental arm, the study will 
have approximately 95% power to detect a relative reduction in incidence of severe OM 
throughout the treatment period in the experimental arm of approximately 34% compared to 
Placebo (i.e., 43% incidence for GC4419 vs 65% for Placebo).  


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12.3. 
Analysis Populations 
Safety and efficacy analyses will be conducted on the ITT population, consisting of all 
randomized subjects who receive at least one dose of GC4419/Placebo, excluding the 28 subjects 
whose dosing was affected by the Sponsor’s dosing suspension decision. Subjects will be 
analyzed according to their randomized treatment assignments. 
Randomized subjects who withdraw prior to any dosing will have their reasons for withdrawal 
noted, and their treatment assignment will remain blinded until the end of the study.  
Analyses on other efficacy populations (e.g., “per protocol” population) may be conducted. Such 
analyses will be specified in the Statistical Analysis Plan for this study. 
12.4. 
Safety Analysis 
AEs 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 and vital signs will be summarized by treatment group at each of the 
protocol-specified time points. 
Safety parameters will be summarized with descriptive statistics on all subjects who received at 
least one dose of GC4419/Placebo. Safety analyses will be conducted on the ITT population and 
the dosing suspension subjects separately.  
Further details will be provided in the study’s Statistical Analysis Plan. 
12.5. 
Primary Efficacy Analysis 
SOM incidence (i.e., the proportion of subjects with SOM) during the Study Treatment Period 
will be compared between the GC4419 and Placebo arms by the Cochran-Mantel-Haenszel 
(CMH) test at a 2-sided Type 1 error rate of 0.05.  
Efficacy analyses will be stratified by the factors used in randomization, namely post-operative 
vs. definitive treatment and planned chemotherapy schedule. 
Details of the primary efficacy analysis will be included in the Statistical Analysis Plan. 
12.5.1. 
Multiplicity 
To control the overall Type 1 error at 0.05, the primary endpoint will first be tested at a two-
sided 0.05 level.  If the primary endpoint result is significant at this level, then Holm-Bonferroni 
multiplicity testing will be conducted on the following proposed secondary endpoints applying a 
familywise two-sided alpha of 0.05:   
• incidence of Grade 4 OM during the Study Treatment Period;  
• total number of SOM days (per subject) during the OM Observation Period for the 
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• total number of days of Grade 4 OM (per subject) during the OM Observation Period 
for the entire study population. 
Further details regarding multiplicity testing will be included in the Statistical Analysis Plan. 
12.5.2. 
Handling of Missing Data 
Subjects who withdraw consent for GC4419/Placebo administration should be encouraged to 
continue and complete standard IMRT/cisplatin, and protocol assessments, notably scheduled 
OM assessments.   
Investigators should make reasonable attempts to continue to collect WHO OM scores for 
inclusion in the study database for subjects who discontinue from GC4419/Placebo, cisplatin, or 
IMRT. 
The study’s Statistical Analysis Plan will discuss the imputation strategy for subjects who lack 
WHO OM scores, who discontinue from the study without complete follow-up of WHO OM 
scores, and whose resolution date of severe OM is unknown. 
12.5.3. 
Covariate Adjustment 
Because the randomization is stratified by baseline post-operative vs definitive treatment status, 
and by planned cisplatin 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 unacceptably small. 
12.6. 
Secondary Efficacy Analyses 
12.6.1. 
Secondary Endpoints 
Secondary endpoints will be analyzed as described in Section 12.5.1; testing will be stratified by 
the factors used in randomization. 
The number of days of SOM, or of Grade 4 OM, will be determined as follows: 
• Subjects who never develop SOM during the OM Observation Period will be judged to 
have zero days of SOM 
• Subjects who never develop Grade 4 OM during the OM Observation Period will be 
judged to have zero days of Grade 4 OM 
• For subjects who do develop SOM or Grade 4 OM, the number of days of SOM or Grade 
4 OM will be taken to include all days from the first observation of SOM or Grade 4 OM 
to the last observation of SOM or Grade 4 OM, with no subsequent SOM or Grade 4 OM 
Additional details will be described in the Statistical Analysis Plan. 
12.7. 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses will be described in the Statistical Analysis Plan. 


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12.8. 
Analysis of Tumor Endpoints 
12.8.1. 
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.   
12.8.2. 
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 of cumulative event rates will be made for time-to-event endpoints (OS, PFS, locoregional 
failure over time, distant metastases over time).   
12.8.3. 
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. 
12.9. 
Interim Analysis 
No interim efficacy analysis is planned. 
An independent Data Monitoring Committee (DMC) will perform periodic unblinded safety 
reviews while subjects in the study receive GC4419/Placebo. 
13. 
ETHICS 
13.1. 
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), ICH guidelines, in particular ICH-GCP, or 
with the laws and regulations of the country in which the research is conducted, whichever 
affords the greatest protection to the study subject. 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. 
13.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, information sheets, or descriptions of the study used to obtain informed consent) 


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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 the Sponsor or its representatives before 
initiating the conduct of any study procedures including screening or enrolling any patients into 
the study. 
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 the Sponsor. Significant protocol deviations will be reported to the 
Sponsor 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. 
13.3. 
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 Informed Consent Form (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. 
13.4. 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will perform periodic unblinded safety 
reviews while subjects in the study receive GC4419/Placebo. 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.  
The details of the DMC meetings and responsibilities are outlined in a separate DMC Charter. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
In accordance with 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 subject 
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. 
 


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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: 
Data are authentic, accurate, and complete; 
Safety and rights of subjects are being protected; 
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 the Sponsor, 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 Sponsor 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, GCP guidelines of the ICH, and any applicable 
regulatory requirements. The Investigator should contact the Sponsor immediately if contacted 
by a regulatory agency about an inspection. 
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 subjects, may be 
made only by the Sponsor 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 the Sponsor 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 the Sponsor.  


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14.5.2. 
Confidentiality 
All information provided by the Sponsor 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 the Sponsor.  
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 the Sponsor.  
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be monitored and managed in accordance with ICH-GCP. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor 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. 
16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Case Report Forms 
All required study data must be recorded on the electronic CRF provided by the Sponsor 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-GCP 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 
subject who is randomized, 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 
subject withdraws from the study, the electronic CRFs should be promptly completed and the 
reason for withdrawal must be noted. If a subject is withdrawn from the study because of a drug-
related toxicity, thorough efforts should be made to clearly document the outcome. 
16.2. 
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 for US sites and 25 years for Canadian sites following the date on 


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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 for US sites and 25 years for Canadian sites 
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 for US sites and 25 years for 
Canadian sites after notification by the Sponsor of the FDA or other applicable regulatory agency 
decision. The records must be available for copying and inspection if requested by regulatory 
authorities. 
The Sponsor 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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neck 32(5): 599-606. 
Trotti, A., Harris, J., et al. (2018). "NRG-RTOG 1016: Phase III Trial Comparing 
Radiation/Cetuximab to Radiation/Cisplatin in HPV-related Cancer of the Oropharynx." 
International Journal of Radiation Oncology, Biology, Physics Supplement, 2018. 
Uno H, Claggett B, Tian L, et al. (2014). "Moving Beyond the Hazard Ratio in Quantifying 
the Between-Group Difference in Survival Analysis." Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 32:2380-2385. 
Vera-Llonch, M., G. Oster, et al. (2006). "Oral mucositis in patients undergoing radiation 
treatment for head and neck carcinoma." Cancer 106(2): 329-336. 
 


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18. 
APPENDICES 
 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Table 6: 
Schedule of Assessments 
Assessments 
Screening 
Treatment 
Follow-up 
Post-IMRT 
OM 
Follow-up 
Long-term Follow-up 
≤28 days 
of IMRT 
Day 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Last Day 
of IMRT 
or Early 
Term1 
Post-IMRT 
Wks 1 & 2  
(±2 D)2 
Months 3, 
6, 9, & 12 
Post-
IMRT 
(±30 D) 
Months 
3 & 12 
Post-
IMRT 
(±30 D) 
Months 16, 20, 
24 Post-IMRT 
(±30 D) 
Baseline 
(IMRT 
Day 1) 
Days 
2-7 
Days  
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Days 
43-49 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dental exam/IMRT clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and HNC histories4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record tobacco use 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Complete physical exam5 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Symptom-directed PE 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Vital signs, ECOG6 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
Record BSA7 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Tumor imaging8 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical tumor assessment9 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Concomitant medications10 
X 
X 
Weekdays 
X 
X 
 
 
 
Adverse Events11 
X 
X 
Weekdays 
X 
X 
 
 
 
ECG (12-lead)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
OM assessment13 
X 
X 
X 
Twice-weekly 
X 
X 
X 
 
 
 
Blood draw: Serum pregnancy test14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw: Lab safety tests15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
 
 
 
 
Blood draw: Serum cotinine17 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Blood draw: PK18 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
Blood draw: Cytokines19 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Blood draw: RNA20 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Dosing GC4419/Placebo21 
 
X 
Weekdays when IMRT is given 
X 
 
 
 
 
BUN, creatinine, and weight 
 
 
 
 
 
X 
 
 
Survival Status22 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
BSA = body surface area; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HNC = head and neck cancer, IMRT = intensity-modulated radiation 
therapy; OM = oral mucositis; PE = physical examination; PK = pharmacokinetics 


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Table footnotes 
1  If a subject ends study participation early and/or withdraws consent after randomization, all last day of IMRT procedures should be completed. 
2 The Post-IMRT Weeks 1 and 2 Follow-up Visits will be scheduled based on the last day of IMRT. All subjects will be seen at 7 ± 2 calendar days from 
the last day of IMRT and 14 ± 2 calendar days from the last day of IMRT.  
3 See protocol Sections 7.1 and 7.2. 
4 The HNC history should include tumor HPV status, staging (AJCC 8th Edition) information, prior treatments, and confirmation of histopathological 
diagnosis of SCC. Medical conditions and illnesses that have occurred since the subject 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), 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. On Day 1 (Baseline) and Day 22, blood pressure must be measured at the following times: 1) within 30 minutes prior to the pre-
GC4419/Placebo PK draw, and 2) after GC4419/Placebo infusion, prior to standing and prior to the End of GC4419/Placebo Infusion PK draw. 
7 For subjects 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 subjects receiving weekly cisplatin, BSA will be recorded to confirm cisplatin dosing at the Baseline Visit and once per week until 
chemotherapy is completed. 
8 Radiographic imaging must be performed within 60 days prior to the first day of IMRT for definitively treated subjects. Imaging can occur prior to the 60-
day window for post-operatively treated subjects. Pre-surgical imaging should be captured if available; post-surgical imaging will be accepted otherwise. 
Imaging must occur at Month 12 post-IMRT for all subjects. Subjects 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. 
9  At the Last Day of IMRT Visit, a clinical tumor assessment will be conducted.  A head/neck/oral exam is sufficient on the Last day of IMRT if disease 
progression is not suspected. If disease progression is suspected, a laryngopharyngoscopy should be conducted. At Months 3, 6, 9, and 12 a 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required to evaluate local/regional or distant progression. However, if 
local/regional progression or recurrence has already been discovered at a previous visit, a laryngopharyngoscopy is no longer required at future visits. If 
distant progression is discovered at a previous visit, a laryngopharyngoscopy is still required at subsequent visits to assess the subject for local/regional 
progression/recurrence. A head/neck/oral exam should always be conducted at Months 3, 6, 9, and 12 post-IMRT. 
10 All concomitant therapies (e.g., prescription and over-the-counter medications) taken by subjects on or after the date of randomization through 30 days 
following the last dose of GC4419/Placebo, IMRT or cisplatin (i.e. whichever occurs last) will be collected in the CRF. Any concomitant therapies used to 
treat any serious or related adverse event will be recorded in the CRF. 
11AEs and SAEs with onset dates on or after the date of randomization through 30 days following the last dose of GC4419/Placebo, IMRT or cisplatin (i.e. 
whichever occurs last) will be recorded on the CRF. All subjects with SAEs will be followed until the events resolve, stabilize, become chronic, the 
subject completes the study, or the subject is lost to follow-up. 
12 Ventricular rate and P-R, QRS, QT, and QTc intervals will be assessed and recorded at Screening. 


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13 All OM assessments must be performed by trained evaluators. The extent of the subject’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 two days apart) within each 5-day IMRT 
period. For Week 1, the first OM assessment will occur at the Baseline Visit and one additional OM assessment must occur at least two days later during 
the week. The extent of the subject’s OM will be scored using the WHO OM toxicity scale. All subjects will be seen at 7 ± 2 calendar days from the last 
day of IMRT and 14 ± 2 calendar days from the last day of IMRT.  
14 For a woman of childbearing potential, serum pregnancy test must be performed at the Screening Visit. 
15 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, magnesium). 
16 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. 
17Blood samples will be collected for serum cotinine test at Baseline (Day 1), once during Week 4, and on the Last Day of IMRT. 
18Blood samples will be collected for GC4419 pharmacokinetic (PK) measurements at Baseline (Day 1), Day 2, and Day 22. See Table 4 for additional 
information. 
19For 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. 
20 If the subject 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. 
21GC4419/Placebo will be administered up to 35 times: weekly, Monday through Friday, beginning at Baseline (IMRT Day 1) and continuing through the 
35th dose. IMRT must begin no longer than 60 min following the end of the GC4419/Placebo infusion. 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. Subjects should resume GC4419/Placebo 
administration when IMRT resumes. If GC4419/Placebo was already administered on a given day and IMRT is not administered due to unforeseen 
circumstances, that day’s GC4419/Placebo dose will still count as one of the 35 doses.  
22Subjects will be followed for survival for two years. The subject’s survival status will be assessed at the following time points: Every 3 months, ± 30 days, 
throughout the 1st year post-IMRT (Months 3, 6, 9, and 12), and Every 4 months, ± 30 days, throughout the 2nd year post-IMRT (Months 16, 20, and 24). 


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APPENDIX 2. WORLD HEALTH ORGANIZATION (WHO) SCORE OF 
ORAL MUCOSITIS 
 
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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APPENDIX 3. 
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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APPENDIX 4. 
NATIONAL CANCER INSTITUTE-COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS, 
VERSION 5.0 
See the following website link for the complete NCI-CTCAE Version 5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf  


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APPENDIX 5. 
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://ascopubs.org/doi/pdf/10.1200/JCO.2017.74.4789 
Table 7: 
Antiemetic Dosing for Adults – High Risk (Cisplatin) 
Drug Class 
Agent 
Dose on Day of 
Chemotherapy 
Dose(s) on 
Subsequent 
Days 
NK1 Receptor Antagonist 
Aprepitant 
125 mg oral 
80 mg oral; days 
2 and 3 
Fosaprepitant 
150 mg IV 
Day 1 only 
Netupitant-
palonosetron 
300 mg netupitant/0.5 mg 
palonosetron 
oral in single capsule 
(NEPA) 
Day 1 only 
Rolapitant 
180 mg oral 
Day 1 only 
5-HT3 Receptor 
Antagonist 
Granisetron 
2 mg oral OR 1 mg OR 
0.01 mg/kg IV OR 1 
transdermal patch OR 10 
mg SC 
Day 1 only 
Ondansetron 
8 mg oral twice daily OR 8 
mg oral dissolving tablet 
twice daily OR three 8 mg 
oral soluble films 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 
 
Corticosteroid if aprepitant 
is used* 
Dexamethasone 12 mg oral OR IV 
8 mg oral OR 
IV; once daily 
on days 2-4* 


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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* 
Corticosteroid if 
netupitant-palonosetron is 
used* 
Dexamethasone 12 mg oral OR IV 
8 mg oral OR 
IV; once daily 
on days 2-4* 
Corticosteroid if rolapitant 
is used 
Dexamethasone 20 mg oral OR IV 
8 mg oral OR 
IV; once daily 
on days 2-4 
Olanzapine 
Olanzapine 
10 mg oral 
10 mg oral on 
days 2-4 
*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. 
MASCC: full updated guidelines may be found at: http://www.mascc.org/antiemetic-guidelines 
(2016)  
For the prevention of non-AC highly emetogenic chemotherapy, a three-drug regimen including 
single doses of a 5-HT3 RA, dexamethasone and an NK1 RA (aprepitant, fosaprepitant, 
netupitant or rolapitant), given before chemotherapy is recommended.  In patients receiving non-
AC highly emetogenic chemotherapy treated with a combination of an NK1 RA, a 5-HT3 RA 
and dexamethasone to prevent acute nausea and vomiting, dexamethasone on days 2–4 is 
suggested to prevent delayed nausea and vomiting.  If aprepitant 125 mg is used in day 1, then 
dexamethasone 8 mg x 1 (days 2-4) + aprepitant 80 mg x 1 (days 2-3) OR dexamethasone 8 mg 
x 2 (days 2-4) + metoclopramide 20 mg x 4  (days 2-4).   Please note that this dosage of 
metoclopramide derives from a phase III study and some regulatory authorities like EMA now 
recommend a maximum 0.5 mg/kg total daily dose.              
 
 


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APPENDIX 6. DAILY ORAL CARE RECOMMENDATIONS 
The following protocol is strongly recommended for all dentulous or partially dentulous study 
participants to optimize oral health during radiation therapy and minimize the risk of post-
radiation dental sequelae. 
1. Diet – Minimize foods that contain refined sugars such as cookies, cakes, candy, sugar-
containing drinks, etc.  Favor fruits and vegetables. 
2. Avoid alcohol, tobacco products, and carbonated beverages. 
3. Practice scrupulous oral hygiene: 
a. Use a soft toothbrush or an electric toothbrush at least twice daily. 
b. Use fluoride-containing toothpaste or fluoride gel. When mouth becomes sore 
from mucositis continue to use toothbrush dipped in bland oral rinse. 
c. Clean spaces between the teeth using dental floss or similar device. 
d. If mouth is too sore to carry this out, rinse with topical anesthetic rinse to ensure 
completion of daily oral care. 
4. Chew sugarless chewing gum after meals. Avoid other forms of chewing gum. 
5. Use bland oral rinse three times a day until mouth becomes sore, then increase to every 
hour when mucositis begins. 
 
Recipe for bland oral rinse: 1 teaspoon salt and 1 teaspoon baking soda in 4 cups of water 
 
 
 


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APPENDIX 7. CYP2D6 SUBSTRATES 
Examples of CYP2D6 Substrates: 
Beta Blockers 
Antidepressants 
Antipsychotics 
Others 
carvedilol 
S-metoprolol 
propafenone 
timolol 
amitriptyline 
clomipramine 
desipramine  
duloxetine  
fluoxetine  
imipramine  
paroxetine 
haloperidol  
risperidone  
thioridazine 
aripiprazole  
atomoxetine  
codeine 
dextromethorphan  
doxepine  
flecainide  
mexiletine  
ondansetron  
oxycodone  
risperidone  
tamoxifen  
tramadol  
venlafaxine 
Reference the following link for a complete and current list of CYP2D6 substrates: https://drug-
interactions.medicine.iu.edu/Clinical-Table.aspx 
 


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APPENDIX 8. SUMMARY OF CHANGES IN AMENDMENT 4 
The GTI-4419-301 Protocol Amendment 3, dated 27 November 2018 is replaced by this Protocol 
Amendment 4, dated 13 July 2020. This Protocol Amendment 4 applies to all sites. 
Listed below is a summary of substantive changes incorporated into Amendment 4.  
Administrative changes, such as cross-linking and typographical/grammatical corrections have 
also been made, which may not be summarized.  A redline version which identifies all non-
formatting changes (i.e., “was-is” document) has been provided to all sites. (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: Updated number of participating sites to 100. 
Rationale: Increase in number of participating sites. 
2. Change: Updated total number of subjects enrolled to 450. 
Rationale: Subject number increased to enhance the statistical power of the study to 
support a more robust statistical finding for a single pivotal efficacy study NDA and to 
support the overall final safety database intended for the marketing application. 
3. Change: Updated estimated enrollment period to 32 months. 
Rationale: Estimate increased due to increase in subject number. 
4. Change: Updated study period. 
Rationale: Study timeline extended due to increase in subject number. 
5. Change: Added study period definitions. 
Rationale: To align between protocol and final Statistical Analysis Plan. 
6. Change: Added information regarding the sponsor’s dosing suspension decision. 
Clarified that the 28 subjects on treatment during the dosing suspension are excluded 
from the ITT. 
Rationale: New information. 
7. Change: Added results from the RTOG 1016 study to background section. 
Rationale: New information. 
8. Change: Clarified that once prepared, GC4419/Placebo saline mixtures should spend as 
little time as possible outside refrigerated conditions, not exceeding more than 6 hours at 
ambient temperature. 
Rationale: Clarification. 
9. Change: Added information regarding description of GC4419 and instructions regarding 
required use of a 0.2 or 0.22 micron syringe filter during preparation of GC4419/Placebo 
or inline filter during administration of GC4419/Placebo to align with the revised 
Pharmacy Manual. 


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Rationale: To align between the protocol and revised Pharmacy Manual the description 
of the filtering requirement in the preparation process as a precautionary measure in the 
event that visible particles are found in the vialed drug product. 
10. Change: Clarified that all medication restrictions begin on Day 1 of IMRT and 
GC4419/Placebo. 
Rationale: Clarification. 
11. Change: Clarified that ventral tongue is included in the list of oral sites in Inclusion 
Criterion 2. 
Rationale: Clarification. 
12. Change: Clarified that Exclusion Criterion 2 is intended to exclude M1 disease (distant 
metastasis). 
Rationale: Clarification. 
13. Change: Clarified that prior induction chemotherapy in Exclusion Criterion 4 refers to 
prior induction chemotherapy for current HNC. 
Rationale: Clarification. 
14. Change: Clarified that history of active hepatitis B/C is exclusionary per Exclusion 
Criterion 12. 
Rationale: Clarification. 
15. Change: Clarified that cumulative incidence of severe OM and of WHO Grade 4 OM are 
defined as the proportion of subjects with any occurrence of WHO Grade 3-4 OM and 
WHO Grade 4 OM respectively. 
Rationale: Clarification. 
16. Change: Clarified pre-treatment imaging requirements. Radiographic tumor imaging 
must occur within 60 days prior to the first day of IMRT (Baseline) for definitively 
treated subjects. Pre-surgical imaging should be used if available for post-operatively 
treated subjects, even if the imaging occurs prior to the 60-day window. If pre-surgical 
imaging was not done, post-surgical imaging can be used. 
Rationale: Clarification. 
17. Change: Clarified that if local/regional progression or recurrence has already been 
discovered at a previous post-IMRT visit, a laryngopharyngoscopy is no longer required 
at future visits. However, if distant progression is discovered at a previous visit, a 
laryngopharyngoscopy is still required at subsequent visits to assess the subject for 
local/regional progression/recurrence. A head/neck/oral exam must always be conducted 
at Months 3, 6, 9, and 12 post-IMRT. 
Rationale: Clarification. 
18. Change: Added blood urea nitrogen (BUN), creatinine, and weight assessments at 3, 6, 
9, and 12 Months post-IMRT. 
Rationale: Additional assessments included to support exploratory analysis. 


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19. Change: Provided clarification and additional detail on secondary and exploratory 
objectives/endpoints. 
Rationale: Updated to align protocol and final Statistical Analysis Plan. 
20. Change: Updated the description of the planned multiplicity testing on the secondary 
endpoints from Hochberg to Holm-Bonferroni. 
Rationale: Updated to align protocol and final Statistical Analysis Plan. 
21. Change: Updated “glutamine applied topically” to “glutamine in any form” under 
prohibited medications. 
Rationale: Clarification per protocol clarification memorandum released 03-Jan-2020. 
22. Change: Added information regarding GC4419 and CYP2D6 drug-drug interaction. 
Rationale: Clarification and update consistent with prior investigator notification.