Clinical trial NCT02324335
Conditions: Head and Neck Neoplasms Mucositis
Keywords: Oral Mucositis Brilacidin Chemoradiation
Sponsor: Innovation Pharmaceuticals, Inc.
Start date: 2014-08-14; Completion date: 2017-11-22
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Oral Mucositis (OM) is a painful and debilitating side effect of many of the drug/radiation regimens used to treat cancer. This study examines the investigational drug brilacidin and its possible application in prevention of oral mucositis in patients undergoing chemoradiation for treatment of head and neck cancer.

Detailed description:
This study will examine whether daily oral rinses with a solution containing brilacidin will prevent the occurrences of OM or lessen the severity of OM if it occurs. Patients will use an oral rinse 3 times daily for up to seven weeks during chemoradiation for head and neck cancer.

Arms: arm 1: Water for Injection arm 2: Brilacidin 3 mg/mL in Water for Injection
Interventions: intervention 1: Brilacidin intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Rinse used 3 times daily for 7 weeks intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL PROTOCOL 
CTIX-BRI-205 
Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Brilacidin Oral Rinse Administered Daily for 
7 Weeks in Attenuating Oral Mucositis in Patients with Head and Neck Cancer 
Receiving Concurrent Chemotherapy and Radiotherapy 
Document type: 
Clinical Protocol - Amended 
Version number: 
1.9  
Version date: 
23 August 2017 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential.             
This information may not be used, published or disclosed without prior written approval from 
Innovation Pharmaceuticals Inc. (formerly Cellceutix Corporation) 
NCT number:
NCT02324335


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Innovation Pharmaceuticals Inc. (formerly Cellceutix 
Corporation) 
Name of Finished Product: Brilacidin Solution, 50 mg/ml (free base) 
Name of Active Ingredient: Brilacidin tetrahydrochloride 
Title of Study:  
Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Efficacy and Safety of Brilacidin Oral Rinse Administered Daily for 7 Weeks in 
Attenuating Oral Mucositis in Patients with Head and Neck Cancer Receiving Concurrent 
Chemotherapy and Radiotherapy 
Study Centers:  
Approximately 20 sites in the United States will participate in the study 
Number of Subjects Planned:  
Approximately 60 subjects with head and neck cancer receiving concurrent chemotherapy 
and radiotherapy 
Study Duration per subject: 
Approximately 17 weeks 
Phase of Development: 
2 
Primary Objective(s): 
•
To evaluate the efficacy of topically applied brilacidin administered three times daily
by oral rinse for approximately 7 weeks (treatment week is defined as a 7-day period,
irrespective of the day of the week that the 7-day period begins) compared to placebo
in reducing the incidence of severe OM (defined as grade 3 or 4 on the WHO Oral
Mucositis scale, WHO Grade ≥3) in subjects with head and neck cancer (HNC)
receiving concomitant chemoradiation therapy (CRT).
•
To evaluate the safety and tolerability of topically applied brilacidin administered
three times daily by oral rinse for approximately 7 weeks (treatment week is defined
as a 7-day period, irrespective of the day of the week that the 7-day period begins).


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Secondary Objectives: 
•
To evaluate the efficacy of topically applied brilacidin in reducing the duration of
severe OM (WHO Grade ≥3) in subjects with HNC receiving concomitant
chemoradiation therapy.
•
To evaluate the efficacy of topically applied brilacidin in delaying the onset of severe
OM (WHO Grade ≥3) in subjects with HNC receiving concomitant chemoradiation
therapy.
Design and Methodology: 
The study is a Phase 2, randomized (1:1 ratio), double-blind, placebo-controlled, 2-arm 
trial to be conducted in patients receiving chemoradiation for the treatment of squamous 
cell carcinoma of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx. 
Patients with this diagnosis whose anticipated treatment includes chemoradiation therapy 
(CRT) and who consent to participate will enter a screening period of up to 45 days prior 
to the anticipated initiation of CRT. If eligible, subjects will be randomized to one of the 
two blinded study treatments and will enter the treatment phase of the study 
(approximately 11 weeks in duration).  
For entry into the study, eligible patients will have recently-diagnosed (in the previous 6 
months), pathologically-confirmed, non-metastatic squamous cell carcinoma of the oral 
cavity, oropharynx, hypopharynx, or supraglottic larynx. Tumor staging for eligibility, 
using AJCC Tumor Staging Guidelines, or as determined by institutional tumor board 
review may be determined from scans (CT, PET, and/or MRI) obtained within 120 days 
prior to consent for screening. Scan interpretation should follow Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 criteria (Appendix E).  
Patients must be scheduled to receive a continuous course of intensity-modulated radiation 
therapy (IMRT) with a minimum cumulative dose of 55 Gray (Gy) and maximum 
cumulative dose of 72 Gy over approximately 7 weeks (treatment week is defined as a 7-
day period, irrespective of the day of the week that the 7-day period begins). Planned 
radiation treatment fields must include at least two oral sites (buccal mucosa, floor of 
mouth, ventral/lateral tongue, soft palate). The treatment plan must include chemotherapy 
with cisplatin administered in standard weekly (30-40 mg/m2) or approximately every 21 
days (80-100 mg/m2) regimens. No other chemotherapy is allowed during radiotherapy 
unless intolerance to cisplatin is demonstrated during study participation. In this case, with 
medical monitor approval, carboplatin may be substituted. 
Eligible subjects will be randomized to receive one of the following study drug regimens 
during participation in the study (1:1 ratio):  
Arm A: Placebo (WFI) [oral rinse tid] 
Arm B: Brilacidin 3 mg/mL in WFI [oral rinse tid] 
The study drug will be administered as an oral rinse three times daily (approximately 6 
hours between oral rinses) beginning on the first day of radiotherapy and continuing each 
day (including weekends) until the completion of the course of chemoradiation. The 


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subject will be instructed to use the study oral rinse three times each day with 
approximately 6 hours between each use, whenever possible. Subjects will be instructed to 
perform the oral rinse for 1-minute and spit out the rinse after each use, avoiding 
swallowing any of the rinse.  The first use of oral rinse on the first day of study drug 
treatment must be witnessed by a member of the study staff. Subjects will be told not to 
eat, brush their teeth, chew gum, or suck on hard candy, cough drops, etc., for at least 10 
minutes before each oral rinse. A subject should rinse his/her mouth with plain water prior 
to administering the oral rinse.  Subjects will be told not to eat, drink, brush their teeth, 
chew gum, or suck on hard candy, cough drops, etc., for 30 minutes following each use of 
the oral rinse.  Subjects who use allowed non-study oral rinse(s) (i.e., Gelclair®, saline 
solutions) during the study period should ensure that the study oral rinse is used at least 
60 minutes after use of a non-study oral rinse and that a non-study oral rinse is not used 
until at least 60 minutes after use of the study rinse. 
Note: Although chemoradiation is complete (i.e. the end of radiation therapy (ERT) visit 
has occurred), subjects are to complete the full 7 days of study drug for Week 7. 
The treatment phase of the study will include: (1) the period of RT treatment with 
concomitant chemotherapy and (2) all assessments occurring after the last dose of RT, 
through and including a Week 4 Post-RT follow-up visit (the EOS visit).  
•
During the CRT treatment period, subjects will be assessed twice weekly for the
presence and severity of OM by trained evaluators using the WHO grading scale for
OM. Subjects will complete a daily study diary (including weekend days). The diary
contains Question 2 of the Oral Mucositis Daily Questionnaire (OMDQ), a record of
daily analgesic use for mouth and/or throat pain, a record of the study drug oral rinses
performed each day, and the subject’s assessment of mouth sensations.  The diary will
be reviewed by a member of the study staff each day during the first week (at least 5
days) of study treatment to ensure that the subject is appropriately completing the
diary. If subject diary completion is satisfactory, then the diary will be reviewed at
least once weekly during the remainder of the study. At weekly intervals (on the same
day of each week), subjects will complete the FACT-H&N instrument to record
quality of life responses.
•
Single samples (venous blood) for assessment of brilacidin plasma concentrations will
be obtained from each subject at weekly intervals during the CRT treatment period.
These blood samples may be obtained at the time of the venipuncture for clinical
laboratory tests as specified by the protocol.
•
For those subjects who have consented to gene analysis, samples of venous blood will
be obtained at baseline, during week 3, and on the last day of radiation.
•
All subjects will be evaluated at 1 week after RT completion (or withdrawal from the
study) for assessment of the presence and severity of OM and other safety
assessments. Subjects having an WHO OM Grade ≥2 at this post-treatment visit will
return to the clinic at weekly intervals until mucositis resolves to WHO OM Grade <2;
subjects having a WHO OM Grade ≤1 may be followed by weekly phone call instead.
During the post-RT period, subjects will continue to complete the daily study diary


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that contains Question 2 of the OMDQ as well as recording analgesic use and subjects 
will complete the FACT-H&N QOL instrument weekly until 4 weeks (± 2 days) post-
RT. In most instances the last study related visit, the End of Study (EOS) visit, will be 
at Week 4 post-RT. 
Patient Eligibility: 
•
Patients with recently diagnosed (within previous 6 months), pathologically-
confirmed, non-metastatic squamous cell carcinoma of the oral cavity, oropharynx,
hypopharynx, or supraglottic larynx.
•
Patients scheduled to receive a continuous course of IMRT over approximately 7
weeks (treatment week is defined as a 7-day period, irrespective of the day of the
week that the 7-day period begins) with a minimum cumulative dose of 55 Gray (Gy)
and maximum cumulative dose of 72 Gy. (IMRT is typically administered as 35
separate radiation treatments).
•
Planned radiation treatment fields must include at least two oral sites (buccal mucosa,
floor of mouth, ventral/lateral tongue, soft palate). The treatment plan must include
chemotherapy with cisplatin administered in either a standard weekly (30-40 mg/m2)
or approximately every 21 days (80-100mg/m2) regimen. No other chemotherapy is
allowed during radiotherapy unless intolerance to cisplatin is demonstrated. In this
case, with medical monitor approval, carboplatin may be substituted.
Inclusion Criteria: 
1. Willing and able to read, understand, and sign an informed consent form (ICF) for the
study approved by the Investigator’s local or a central Institutional Review Board
(IRB) or Independent Ethics Committee (IEC) prior to the initiation of any study-
related procedures.
2. Males or females aged ≥18 years on day of consent.
3. Have recently-diagnosed (within previous 6 months pathologically-confirmed, non-
metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or
supraglottic larynx. The treatment planned will utilize CRT therapy as first line non-
surgical treatment. Scans (CT, PET, and/or MRI) obtained within 120 days prior to
consent for screening can be used to determine the patient’s eligibility.
Note: Post-surgical subjects may be enrolled provided any head/neck surgical sites
(including sites of dental extractions) are sufficiently healed.
4. Have a plan to receive a continuous course of conventional external beam irradiation
delivered by intensity-modulated radiation therapy (IMRT) as single daily fractions of
2.0 Gy to 2.2 Gy with a cumulative radiation dose ≥55 Gy and ≤72 Gy. Planned
radiation treatment fields must include at least two oral sites (buccal mucosa, floor of
mouth, ventral/lateral tongue, soft palate)
Note: The independent RTQA consultant must confirm that the planned radiation
treatment meets the protocol criteria.


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5. Have a plan to receive a standard cisplatin chemotherapy regimen administered weekly
(30-40 mg/m2) or approximately every 21 days (80-100 mg/m2)
6. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
2. However, potential subjects with an ECOG Performance Status of 3 may be enrolled
provided their condition does not preclude performing the actions required by study
participation (e.g. opening medication bottles, swishing the oral rinse and spitting out,
completing or participating in completion of daily diaries and FACT-H&N forms).
7. Have adequate hematopoietic, hepatic, and renal function at screening:
a.
Hematopoietic function
i. Hemoglobin ≥ 9 g/dL
ii. Absolute neutrophil counts (ANC) ≥ 1.5 x 103/uL
iii. Platelet count ≥ 100 x 103/uL
b. Hepatic function
i. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0
times the ULN
c.
Renal function
i. Either a serum creatinine concentration within the site laboratory’s normal
limits or a calculated creatinine clearance > 60 mL/min
8. Urine or serum pregnancy test: negative for female patients of childbearing potential. If
pregnancy test is performed more than 10 days prior to the start of radiotherapy, the
test must be repeated prior to Day 1.
9. Female subjects with reproductive potential must agree to use reliable means of
contraception (e.g., abstinence, double barrier method, oral/implantable/transdermal
contraception, Depo-provera, intrauterine device, or physical barrier) throughout study
participation and for 90 days after the last use of study oral rinse.
A female is considered of reproductive potential unless she is premenarchal, without a
uterus and/or both ovaries, or has had a bilateral tubal ligation, has undergone the
Essure procedure with confirmation of tubal blockage, or is postmenopausal. Females
identified as postmenopausal for less than 2 years must have serum Follicle
Stimulating Hormone (FSH) of 40 mIU/mL or greater at the Screening visit to be
considered postmenopausal.
Exclusion Criteria: 
1.
Has tumor(s) of the lips, sinuses, salivary glands, nasopharynx, glottic larynx, subglottic
larynx, or unknown primary tumor
2.
Has metastatic disease (M1) Stage IV C
3.
Has had prior radiation to the head and neck for any reason/condition
4.
Plan to be treated with cetuximab (Erbitux®) and not cisplatin as the component of
chemoradiation


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5.
Planned use of cisplatin as induction chemotherapy.
6.
Has a history of other malignant tumors within the last 5 years, except non-melanoma
skin cancer or in situ cervical carcinoma curatively excised
7.
Has had a major surgical procedure, other than for HNC, or significant traumatic injury
within 4 weeks prior to the initiation of RT; anticipation of need for major surgical
procedure during the course of the study
8.
Will have incompletely healed sites of dental extractions on first day of chemoradiation
treatment
9.
Has a 12-lead ECG obtained at screening visit which shows medically significant
abnormality(ies) (e.g. left bundle branch block, frequent premature ventricular
contractions, QTc interval prolongation > 450 msec for males and > 470 msec for
females)
10. Has untreated hypertension or has hypertension under treatment meeting one of the
following definitions:
a.
Age ≥ 60 years: SBP ≥ 150 mmHg and/or DBP ≥ 90 mmHg
b. Age < 60 years: SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg
c.
All ages with diabetes: SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg
NOTE: Medical therapy for untreated hypertension may be initiated or existing 
treatment for hypertension may be optimized during the Screening Phase if clinically 
indicated. Blood pressures will then be reassessed before Day 1 to confirm eligibility. 
Blood pressure criteria need to be met at screening and/or prior to dosing on Day 1. 
11. Has active infectious disease undergoing systemic treatment, excluding oral candidiasis
12. Has oral mucositis (of any severity) prior to initiation of radiotherapy
13. Has a diagnosis of an immunosuppressive illness or a condition requiring chronic
immunosuppression
14. Has known seropositivity for HIV or hepatitis C antibody, or known to be hepatitis B
surface antigen positive (testing for these serologic markers is not required for
enrollment in this protocol)
15. Use of any investigational agent within 30 days of randomization
16. Is pregnant or breastfeeding
17. Has known allergies or intolerance to brilacidin, cisplatin, or carboplatin
18. Has inability to give informed consent or comply with study requirements
19. Has any other condition or prior therapy that in the opinion of the Investigator would
make the patient unsuitable for the study and/or unable to comply with requirements for
follow-up visits.
20. Is unwilling or unable to agree to swish and spit the study oral rinse three times per day
during the study period


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Test Product, Dose, and Mode of Administration: 
Brilacidin (45 mg/ 15mL WFI) oral rinse tid, or placebo (15mL WFI) oral rinse tid 
Efficacy and Safety Endpoints: 
Primary Efficacy Endpoint 
Incidence of severe OM (WHO Grade ≥3) experienced during radiation therapy by subjects 
with HNC receiving concomitant chemoradiation therapy and a cumulative radiation dose 
of at least 55 Gy. 
Secondary Efficacy Endpoints 
•
Duration of severe OM (WHO Grade ≥3), from initial WHO Grade ≥3 during radiation
therapy to the first WHO Grade 2 or lower OM assessment during/after radiation
therapy.
•
Duration of severe OM (WHO Grade ≥3), from initial WHO Grade ≥3 during radiation
therapy to the last WHO Grade ≥3 assessment during/after radiation therapy.
•
Time to onset of severe OM (WHO Grade ≥3).
•
Incidence of severe OM (WHO Grade ≥3) by cumulative IMRT.
Safety Endpoints 
The safety and tolerability of treatment with brilacidin will be assessed through incidence, 
severity and type of adverse events, including serious adverse events, and changes in 
clinical laboratory parameters, blood pressure, heart rate, ECOG, and body weight. 
Systemic Exposure/Pharmacokinetic Endpoints 
Brilacidin systemic exposure will be estimated from plasma sample concentrations; 
samples will be obtained from each randomized subject at weekly intervals during the CRT 
treatment period. 
Data Analysis: 
Efficacy Analyses 
Full details of the statistical methodology for summary and analyses of the data collected 
in this study will be prepared separately from this protocol in a Statistical Analysis Plan 
(SAP). 
The primary efficacy objective is to evaluate brilacidin compared to placebo in reducing 
the incidence of severe OM (defined as grade 3 or 4 on the WHO Oral Mucositis scale, 
WHO Grade ≥3) in subjects with HNC receiving concomitant chemoradiation therapy and 
a cumulative radiation dose of at least 55 Gy. For this comparison the Fishers Exact Test 
will be used. 
Time to onset of severe OM (WHO Grade ≥3) will be assessed using the log rank test. Both 
a scale of days, and a scale of cumulative radiation dose delivered (Gy) will be used for the 


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Kaplan-Meier analysis. The log rank test will be used to compare treatment groups at time 
of onset of severe OM. Time to onset of ulcerative OM (WHO Grade ≥2) will be explored 
similarly. 
Duration of severe OM (WHO Grade ≥3) is evaluated two different ways: (1) Initial instance 
duration of severe OM is defined as the number of days from initial WHO Grade ≥3 during 
radiation therapy until the first WHO Grade 2 or lower OM Grade occurs; (2) Overall 
duration of severe OM is defined as the number of days from initial WHO Grade ≥3 during 
radiation therapy to the last WHO Grade ≥3 assessment during/after radiation therapy. If 
any subject does not experience severe OM, his/her duration will be set to 0. Subjects who 
experience severe OM but do not resolve to WHO Grade 2 or lower will be censored at the 
last study visit. The effect of treatment on the duration of severe OM will be assessed using 
a log rank statistic. Analyses will be done using both a scale of days, and a scale of 
cumulative radiation dose delivered (Gy). 
Safety Analysis 
All safety data, demographic and baseline characteristics will be summarized descriptively 
through appropriate data tabulations, descriptive statistics, and categorical summaries. 
Changes in blood pressure, heart rate, and hematology and clinical chemistry parameters 
from baseline to the end of the study will be summarized. Treatment-emergent changes from 
values within normal range to abnormal values in clinical laboratory parameters will be 
identified by means of summary and shift tables. ECOG and body weight changes from 
baseline to the end of the study will also be summarized. 
Interim Analysis 
Ad-hoc interim analyses may be conducted to support decision making concerning the 
current clinical study, the Sponsor's clinical development projects in general or in case of 
any safety concerns. Such analyses may be unblinded, and the details will be documented 
in the SAP. 
Sample Size 
The proportion of subjects experiencing severe OM (WHO Grade ≥3) after a total 
cumulative radiation dose of at least 55 Gy (and no more than 72 Gy) is unknown but 
expected to be approximately 75% for the placebo oral rinse treatment group, and the 
assumption for the active Brilacidin oral rinse treatment group is estimated to reduce to 
approximately 35-40%. Based on these assumptions, a sample size of 23-30 subjects per 
treatment group is appropriate to detect the specified difference with at least 80% power.