Clinical trial NCT02990468
Conditions: Head and Neck Cancer
Keywords: Mucositis Xerostomia
Sponsor: BioMimetix JV, LLC
Start date: 2017-04-19; Completion date: 2022-03-31
Enrollment: 29 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1 / Phase 2 study of newly diagnosed patients with biopsy-proven head and neck cancer (squamous cell carcinoma) who are undergoing standard radiation therapy and treatment with cisplatin. BMX-001 added to radiation therapy and cisplatin is expected to reduce radiation-induced mucositis and xerostomia and also has the potential to benefit the survival of head and neck cancer patients. In Phase 1, safety and tolerability of BMX-001 will be assessed using a Continual Reassessment Method (CRM) and a maximum tolerated dose (MTD) will be determined. BMX-001 will be given subcutaneously first with a loading dose zero to four days prior to the start of chemoradiation and followed by twice a week doses at one-half of the loading dose for the duration of radiation therapy plus two weeks. In Phase 2 both safety and efficacy of BMX-001 will be evaluated. Impact on mucositis and xerostomia will also be assessed. A maximum of 48 patients will be enrolled to the MTD dose determined in Phase 1 to confirm the MTD. The investigators hypothesize that BMX-001 when added to standard radiation therapy and cisplatin will be safe at pharmacologically relevant doses in patients with newly diagnosed head and neck cancer. The investigators also hypothesize that in Phase 2 of this study the addition of BMX-001 will reduce the severity of radiation-induced mucositis and xerostomia in patients receiving head and neck radiation therapy.

Detailed description:

Arms: arm 1: In Phase 1, safety and tolerability of BMX-001 will be assessed using a Continual Reassessment Method and a maximum tolerated dose (MTD) will be determined using a single arm design. In Phase 2, the severity of radiation-induced mucositis and xerostomia will be assessed using a single arm design.
Interventions: intervention 1: BMX-001 intervention 2: Radiation Therapy intervention 3: Cisplatin
Intervention descriptions: intervention 1: Subcutaneous injection. intervention 2: Patients will receive standard dose intensity modulated radiation therapy (IMRT). intervention 3: Cisplatin will be administered per institution's standard of care practice.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #: BMX-HN-001 
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Protocol #: BMX-HN-001 
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, 
and BMX-001 in Locally Advanced Head and Neck Cancer 
Sponsor: 
BioMimetix JV, LLC 
Funding Source: 
National Cancer Institute – SBIR Contract to 
BioMimetix JV, LLC 
Medical Monitor: 
Elizabeth A. Regan, MD, PhD 
BioMimetix JV, LLC 
5340 South Quebec Street 
Suite 345N 
Greenwood Village, CO 80111 
303-921-1880 (cell)
elizabeth.regan@bmxpharma.com 
NCT02990468




Protocol #: BMX-HN-001 
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1 
Signature Page 
 
 
SPONSOR SIGNATURE PAGE 
 
Protocol number: 
BMX-HN-001 
Version: 
6.0 
Protocol Title: 
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-
001 in Locally Advanced Head and Neck Cancer  
Version Date: 
April 30, 2019 
Approved by: 
 
 
 
 
 
 
 
 
James D. Crapo, MD 
Manager, BioMimetix JV, LLC 
 
Date 
 
 
 
Shayne Gad, PhD 
Authorized Signature on behalf of IND Sponsor 
 
Date 
 
1 May 2019


Protocol #: BMX-HN-001 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol number: 
BMX-HN-001 
Version: 
6.0 
Protocol Title: 
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-
001 in Locally Advanced Head and Neck Cancer  
Version Date: 
April 30, 2019 
 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the study drug supplied by the Sponsor will be used only as described in the 
protocol named above. 
 
 
 
 
 
 
 
 
Principal Investigator Name Signed 
 
 
 
Date 
Principal Investigator Name Printed 
 
 
 
 
Clinical Center 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1 Signature Page ....................................................................................................................................... 2 
Table of Contents ....................................................................................................................................... 4 
2 List of Abbreviations .............................................................................................................................. 9 
3 Schema of Clinical Trial ........................................................................................................................ 11 
4 Introduction ......................................................................................................................................... 12 
4.1 
Head and Neck Cancer .................................................................................................................. 12 
4.1.1 
Disease ............................................................................................................................... 12 
4.1.2 
Radiation-induced Damage ................................................................................................. 12 
4.2 
BMX-001 ....................................................................................................................................... 12 
4.3 
Study Design ................................................................................................................................. 14 
4.3.1 
Phase 1- Completed............................................................................................................ 15 
4.3.2 
Phase 2 ............................................................................................................................... 15 
4.4 
Rationale ....................................................................................................................................... 16 
4.4.1 
Study Rationale .................................................................................................................. 16 
4.4.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration .................................... 16 
4.5 
Quality of Life and Function Assessments ...................................................................................... 16 
5 Objectives ............................................................................................................................................ 19 
5.1 
Phase 1 ......................................................................................................................................... 19 
5.1.1 
Primary Objective ............................................................................................................... 19 
5.1.2 
Secondary Objectives ......................................................................................................... 19 
5.1.3 
Exploratory Objective ......................................................................................................... 19 
5.2 
Phase 2 Endpoints ......................................................................................................................... 19 
5.3 
Phase 2 Objectives ........................................................................................................................ 19 
5.3.1 
Secondary Objective ........................................................................................................... 20 
5.3.2 
Exploratory Objectives ........................................................................................................ 20 
6 Patient Selection .................................................................................................................................. 21 
6.1 
Inclusion Criteria ........................................................................................................................... 21 
6.2 
Conditions for Patient Ineligibility (Exclusion Criteria) .................................................................... 22 
7 Pretreatment Evaluations/Management .............................................................................................. 24 
7.1 
Informed Consent ......................................................................................................................... 24 
7.2 
Screening Examination .................................................................................................................. 24 
8 Registration Procedures and Administrative Considerations................................................................. 25 
8.1 
Enrollment Procedure ................................................................................................................... 25 


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8.2 
Regulatory and Ethical Compliance................................................................................................ 25 
8.3 
Institutional Review Board and Protocol Review ............................................................................ 25 
8.4 
Privacy, Confidentiality, and Data Storage ..................................................................................... 25 
8.5 
Protocol Amendments .................................................................................................................. 25 
8.6 
Conflict of Interest ........................................................................................................................ 26 
9 Radiation Therapy ................................................................................................................................ 27 
9.1 
Dose Specification For Clinically Measurable Disease..................................................................... 27 
9.2 
Technical Factors ........................................................................................................................... 29 
9.2.1 
Treatment Planning/Delivery .............................................................................................. 29 
9.2.2 
Image Guidance for IGRT .................................................................................................... 29 
9.3 
Localization, Simulation, and Immobilization ................................................................................. 29 
9.4 
Treatment Planning/Target Volumes ............................................................................................. 29 
9.4.1 
Definition of Target Volumes for Unresected Patients (Who Receive Definitive 
Chemoradiation) ........................................................................................................................... 29 
9.4.2 
Definition of Target Volumes for Post-Operative Patients ................................................... 30 
9.4.3 
Definition of Normal Tissues/Organs at Risk (OAR) ............................................................. 31 
9.4.4 
IMRT Dose Constraints to Normal Structures ...................................................................... 32 
9.5 
Critical Structures .......................................................................................................................... 33 
9.6 
Documentation Requirements for IMRT Approach ........................................................................ 34 
9.7 
RT Quality Assurance Reviews ....................................................................................................... 35 
9.7.1 
Radiation Therapy / Adverse Events ................................................................................... 35 
10 Study Drug (Cisplatin)........................................................................................................................... 37 
10.1 Description .................................................................................................................................... 37 
10.2 Formulation .................................................................................................................................. 37 
10.3 Storage and Stability ..................................................................................................................... 37 
10.4 Administration .............................................................................................................................. 37 
10.5 Dose Modifications ....................................................................................................................... 37 
10.5.1 
Suggested dose modifications ............................................................................................ 37 
10.5.2 
Hematologic Toxicity .......................................................................................................... 38 
10.5.3 
Non-hematologic Toxicity ................................................................................................... 38 
10.6 Adverse Events .............................................................................................................................. 39 
10.6.1 
Risks of Phlebotomy ........................................................................................................... 40 
10.7 Supply ........................................................................................................................................... 40 
11 STUDY DRUG (BMX-001) ...................................................................................................................... 41 
11.1 Names, Classification, and Mechanism of Action ........................................................................... 41 


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11.2 Potential Benefits .......................................................................................................................... 41 
11.3 Packaging and Labeling ................................................................................................................. 41 
11.3.1 
Drug Product Formulation and Manufacture ...................................................................... 41 
11.3.2 
Labels for BMX-001 for Injection, 10 mg/mL ....................................................................... 42 
11.3.3 
Syringe and Label for Administration of BMX-001 for Injection, 10 mg/mL ......................... 42 
11.3.4 
Multi-Dose Kits ................................................................................................................... 42 
11.4 Supply, Receipt, and Storage ......................................................................................................... 43 
11.4.1 
Compliance and Accountability ........................................................................................... 43 
11.4.2 
Disposal and Destruction .................................................................................................... 43 
11.4.3 
Dispensing and Preparation ................................................................................................ 43 
11.5 Phase 1 Administration by Dose Escalation at levels below established MTD ................................. 43 
11.6 Phase 2 Expanded ......................................................................................................................... 44 
11.7 Compliance and Accountability ..................................................................................................... 45 
11.8 Concomitant Medications ............................................................................................................. 45 
11.9 Dose Modifications ....................................................................................................................... 45 
11.10 Management Guidelines for Potential BMX-001-induced Toxicities ............................................... 46 
11.10.1 
Post Drug Administration Monitoring ............................................................................. 46 
11.10.2 
Hypotension ................................................................................................................... 46 
11.10.3 
Local Skin Reaction ......................................................................................................... 47 
11.10.4 
Prolongation of QTc Interval and Management ............................................................... 47 
11.11 Dose-Limiting Toxicity (DLT) .......................................................................................................... 48 
11.11.1 
Non-hematologic ............................................................................................................ 48 
11.11.2 
Hematologic ................................................................................................................... 48 
11.11.3 
Other Considerations ...................................................................................................... 49 
11.12 Adverse Events .............................................................................................................................. 49 
11.13 Risk Classification .......................................................................................................................... 50 
12 Other Therapy...................................................................................................................................... 51 
12.1 Permitted Supportive Therapy ...................................................................................................... 51 
12.2 Prohibited Therapies ..................................................................................................................... 51 
13 Screening and On-Study Tests and Procedures ..................................................................................... 53 
13.1 Evaluations During Treatment ....................................................................................................... 54 
13.1.1 
Treatment Period ............................................................................................................... 54 
13.1.2 
Physical Exam ..................................................................................................................... 55 
13.1.3 
Blood Pressure ................................................................................................................... 55 
13.1.4 
ECG .................................................................................................................................... 55 


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13.1.5 
Mucositis ............................................................................................................................ 55 
13.1.6 
Xerostomia ......................................................................................................................... 55 
13.2 Re-treatment Criteria .................................................................................................................... 56 
13.3 Follow-up Period ........................................................................................................................... 56 
13.4 Early Withdrawal of Subject(s)....................................................................................................... 56 
13.4.1 
Criteria for Early Withdrawal .............................................................................................. 56 
13.4.2 
Follow-up Requirements for Early Withdrawal .................................................................... 56 
13.5 End of Treatment .......................................................................................................................... 56 
13.6 End of Study .................................................................................................................................. 57 
13.6.1 
Early Study Termination ..................................................................................................... 57 
13.7 Outcomes Criteria ......................................................................................................................... 57 
13.7.1 
Time-to-Event Variables ..................................................................................................... 57 
13.7.2 
Radiographic Response ....................................................................................................... 57 
13.8 Quality of Life and Functional Assessments: HRQoL ....................................................................... 58 
14 Safety Monitoring and Reporting ......................................................................................................... 59 
14.1 Adverse Events .............................................................................................................................. 59 
14.1.1 
Reporting of AEs ................................................................................................................. 59 
14.2 Serious Adverse Events ................................................................................................................. 59 
14.2.1 
Reporting of SAEs ............................................................................................................... 60 
14.3 External Data and Safety Monitoring Board (DSMB) ...................................................................... 61 
14.4 Monitoring .................................................................................................................................... 61 
14.5 Audits............................................................................................................................................ 61 
15 Data Management and Processing ....................................................................................................... 63 
15.1 Study Documentation.................................................................................................................... 63 
15.2 Case Report Forms (CRFs) .............................................................................................................. 63 
15.3 Data Management Procedures and Data Verification .................................................................... 63 
15.4 Coding ........................................................................................................................................... 63 
15.5 Study Closure ................................................................................................................................ 64 
15.6 Records Retention ......................................................................................................................... 64 
16 Statistical Methods and Data Analysis .................................................................................................. 65 
16.1.1 
Analysis Sets ....................................................................................................................... 65 
16.1.2 
Patient Demographics and Other Baseline Characteristics .................................................. 65 
16.1.3 
Treatments ......................................................................................................................... 65 
16.1.4 
Phase 1 Dose Escalation ..................................................................................................... 65 
16.1.5 
Objectives .......................................................................................................................... 65 


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16.2 Phase 2 ......................................................................................................................................... 67 
16.2.1 
Primary Endpoint................................................................................................................ 67 
16.2.2 
Objectives/Endpoint and Data Analyses .............................................................................. 67 
16.2.3 
Interim Analysis for Phase 2 ................................................................................................ 69 
16.2.4 
Sample Size Calculation for Phase 2 .................................................................................... 69 
17 References ........................................................................................................................................... 70 
Appendix A: Functional Assessment of Cancer Therapy – Head and Neck (Version 4) ................................ 74 
Appendix B: Oral Mucositis Weekly Questionnaire – HN ........................................................................... 77 
Appendix C: Xerostomia-Related Quality of Life Scale ............................................................................... 79 
Appendix D: Dermatology Life Quality Index ............................................................................................. 80 
Appendix E: PRO-CTCAE-HN ........................................................................................................................ 0 
 
 


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2 
List of Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AMRI 
Albany Molecular Research, Inc. 
AP 
Anterior-Posterior 
AST 
Aspartate Aminotransferase 
BED2 
Biologically Equivalent Dose in 2 Gy fractions 
BID 
Twice daily 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRT 
Radiation Treatment and Concurrent Cisplatin 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTQA 
Clinical Trials Quality Assurance 
CTV 
Clinical Target Volume 
DLQI 
Dermatology Quality of Life Index 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
EQD2 
2 Gy-per-fraction Equivalent Dose 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
Functional Assessment of Cancer Therapy-General  
FACT-HN 
Functional Assessment of Cancer Therapy – Head & Neck (Version 4) 
GMP 
Good Manufacturing Practice 
GTV 
Gross Tumor Volume 
Gy 
Gray 
HIF-1 
Hypoxia-inducible factor-1 
HNSCC 
Head and neck squamous cell carcinoma 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
HRQoL 
Health-Related Quality of Life 
IMRT 
Intensity Modulated Radiotherapy 
IGRT 
Image-Guided Radiotherapy 
kV 
Kilovoltage 
KPS  
Karnofsky Performance Scale 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MnSOD 
Manganese Superoxide Dismutase 


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MOS 
Median Overall Survival 
MRI  
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MV 
Megavoltage 
NCI 
National Cancer Institute 
NFĸB  
Nuclear Factor Kappa B 
NRG 
NRG Oncology 
OAR 
Organs at Risk 
OMWQ-HN 
Oral Mucositis Weekly Questionnaire – Head & Neck 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PA 
Posterior-Anterior 
PD 
Progressive Disease 
PEG 
Prophylactic Gastrostomy Tube 
PET 
Positron Emission Tomography 
PFS 
Progression-free Survival 
PFS-6 
Progression-free Survival at 6 months 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PRO-CTCAE 
Patient-Reported Outcome version of the Common Terminology Criteria for 
Adverse Events 
PRV 
Planning Risk Volume 
PTV 
Planning Target Volume 
QoL 
Quality of Life 
RP2D 
Recommended Phase 2 Dose 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SCCHN 
Squamous Cell Carcinoma Head and Neck 
SD 
Stable Disease 
SIB 
Simultaneous Integrated Boost 
SOC 
Standard of Care 
SOD 
Superoxide Dismutase 
SQ 
Subcutaneous 
TDP 
Torsades de pointes 
UAP 
Unanticipated problems 
ULN 
Upper limit of normal 
VMAT 
Volumetric-Modulated Arc Therapy 
XeQoLS 
Xerostomia-Related Quality of Life Scale 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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3 
Schema of Clinical Trial 
 
 
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and 
BMX-001 in Locally Advanced Head and Neck Cancer 
 
 
Figure 1. Schema of Clinical Trial 
 
 
Patient Population: (See Section 6 for Eligibility Criteria) 
Pathologically proven diagnosis of head and neck cancer (squamous cell carcinoma) requiring 
radiation and concurrent cisplatin chemotherapy. 
Sample Size Phase 1: 6  
Maximum Sample Size Phase 2: 48  
 
Post-op in the above schema refers to subjects who have had tumor resection and are being 
scheduled for post-operative radiation therapy and chemotherapy.  
Definitive Therapy in the above schema refers to subjects who have not undergone tumor 
resection but are being scheduled for primary radiation therapy and chemotherapy designed to 
be the definitive approach to their treatment program. 


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4 
Introduction 
4.1 
Head and Neck Cancer 
4.1.1 
Disease 
In 2013 the American Cancer Society estimated there would be 50,000 newly diagnosed cases of 
head and neck squamous cell carcinoma (HNSCC). Radiation therapy and concurrent cisplatin 
(CRT) play a prominent role in the treatment of this disease [1]. This regimen is effective in 
killing the tumor; however, the normal tissues in the mouth and throat are highly sensitive to 
radiation that can lead to severe side effects [2]. These side effects include: xerostomia (dry 
mouth), mucositis (inflammation and sores forming in the mouth), swelling, dysphagia, pain, 
infections, cavities, hair loss, and reddening of the skin. Some of these side effects may be 
severe enough to require feeding tube placement and detrimentally prolong the time required 
to complete a course of therapy. Amifostine (Ethyol®) is the only FDA approved radioprotector 
against radiation-induced xerostomia. Its value in preventing this side effect in a CRT setting is 
uncertain and it has minimal effect against mucositis. 
4.1.2 
Radiation-induced Damage 
Radiotherapy for the treatment of head and neck cancers can produce severe therapy-induced 
side effects. Acute effects commonly appear within a week of starting radiotherapy and most 
people suffer from at least one of these unwanted side effects. The acute side effects can 
include: xerostomia, mucosal degradation (mucositis) and ulceration, edema, loss of taste 
(dysgeusia), difficulty swallowing and talking, ear aches, infections, hair loss, and radiation 
dermatitis. These acute problems can become so severe that radiation therapy has to be 
delayed, which can lead to reduced local control or at times, terminated. Long-term compli-
cations from radiation therapy directed to the head and neck region can include trismus 
(restriction on opening of the jaw), osteoradionecrosis, or breakdown of the mandible, loss of 
sensation, loss of taste, increased risk of dental caries (cavities), and decreased salivary function. 
Thus, quality of life can be severely compromised following the treatment of head and neck 
cancers. More concerning is the increase in non-cancer-related deaths in patients treated with 
concurrent high dose cisplatin and radiation in RTOG 91-11 as a result of long-term complica-
tions. This damage can occur anytime during radiation therapy and has been reported years 
after treatment. The long-term toxicities are a function of high dose radiation and volume of 
irradiated tissue, amplified by the addition of radio-sensitizing chemotherapy. Once the damage 
of normal tissue begins, it is usually progressive and irreversible. Because there is a 50-85% five 
year survival rate for patients treated for head and neck cancers, due in part to a rapidly 
increasing segment of younger patients experiencing HNSCC related to human papillomavirus 
infection, there are many people who are living with these long-term side effects (American 
Cancer Society, 2013 Statistics). Thus, the development of an effective radio-protector would 
improve the quality of life of many head and neck cancer patients. 
4.2 
BMX-001 
It is well established that induction of oxidative stress after radiation therapy (RT) and chemo-
therapy plays a major role in tumor and normal tissue therapy responses [3,4]. Ironically, the 
responses in tumor tend to protect vascular endothelium and tumor cells from RT damage [5], 
whereas these same stresses after RT promote normal tissue damage [3,6]. A variety of 
approaches have been investigated to mitigate oxidative stress post irradiation, including the 


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free radical scavenger, amifostine [7-9]. Although this agent is approved for this use, its daily use 
is limited by side effects [7-9]. In addition, this agent was used primarily to protect salivary 
tissue rather than as a protectant against mucositis or dermatitis and with the advent of salivary 
sparing radiation techniques, this approach has fallen out of favor. Other agents that have been 
tested pre-clinically and clinically include nitroxides and genistein, but these are not currently 
approved for protection against normal tissue injury post-irradiation and neither provides 
catalytic inactivation of reactive species responsible for oxidative stress [7]. Over the past 20 
years, Dr. Ines Batinic-Haberle and colleagues have developed a class of manganese (Mn) 
Porphyrin-based compounds that: 1) are potent anti-inflammatory agents and 2) catalytically 
inactivate a range of reactive oxygen species, including peroxynitrite and superoxide anion [10-
12]. These properties give this class of compound the unique function of protecting normal 
tissues while also augmenting tumor killing in patients undergoing radiation and chemotherapy. 
In addition to inactivation of reactive oxygen species, these drugs inhibit transcriptional activity 
of stress-induced pathways by either eliminating reactive oxygen species that activate stress 
responses or by indirectly preventing activation. Transcription factors known to be inhibited by 
this class of metalloporphyrin include HIF-1 [13,14], NFĸB [15], SP-1 [16] and AP-1 [10]. The most 
recently developed compound, BMX-001 (MnTnBuOE-2-PyP5+), is among the most highly potent 
in a series of well over two dozen metalloporphyrins that have been evaluated thus far [17]. 
BMX-001 is lipophilic and crosses the blood-brain barrier. This drug has been licensed for 
commercial development and will be the lead compound for this project. 
Metalloporphyrins have been shown to protect mice from total body irradiation toxicity [18] and 
xerostomia following parotid gland irradiation [19]. Radiation-induced lung injury was protected 
against by administration of metalloporphyrins in rhesus macaques [20]. Additionally, 
metalloporphyrins have been shown to protect against a range of CNS conditions associated 
with inflammation, including stroke [21] and spinal cord damage [22-24]. Relevant to this 
application, Dewhirst and colleagues showed protection against inflammation (mucositis) and 
decreased saliva production (xerostomia) after a single dose of 13 Gy RT. In this study, C57BL/6J 
mice were exposed to 13 Gy of irradiation with and without concurrent BMX-001. At 10 days 
post-RT, mice that had been treated with BMX-001 and RT had decreased mucositis as 
measured by an inflammation-detecting fluorescent probe, ProSense 750EX, in comparison to 
mice that received only RT without BMX-001. Additionally, at 6 weeks post-RT, xerostomia was 
not as pronounced in animals treated with BMX-001 as compared to mice that received only RT 
without BMX-001. Thus, saliva production ability was preserved and salivary inflammation was 
prevented in mice irradiated with 13 Gy and treated with BMX-001. 
In tumors, Dewhirst and colleagues showed that RT and chemotherapy increase oxidative stress, 
driving upregulation of HIF-1 [5,25], a transcription factor that promotes endothelial and tumor 
cell survival and increases tumor aggressiveness [26]. Radiation creates persistent oxidative 
stress in surviving cells, which upregulates NFkB [27]; this transcription factor also drives 
treatment resistance [28]. Treatment with this new class of metalloporphyrin prevents HIF-1 
and NFkB upregulation in tumors after RT and chemotherapy and improves tumor treatment 
responses [18]. The effect of BMX-001 has been studied on mouse flank xenografts using human 
hypopharnygeal squamous cell carcinoma (FaDu). In this study by Dewhirst and colleagues, FaDu 
tumor size was not significantly changed in the presence of BMX-001 without irradiation. 
However, in the presence of irradiation, BMX-001 significantly inhibited FaDu growth in nude 
mice. In addition, BMX-001 significantly increased the survival of the tumor bearing animals. The 
average time to euthanasia (tumor volume>1500 mm3) for irradiated alone animals was 49.8 


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days, and mice irradiated with BMX-001 had an average survival of 63 days. Thus, BMX-001 did 
not protect head and neck tumor cells from radiation sensitization; in fact, BMX-001 further 
sensitized the head and neck tumor to irradiation and enhanced the survival of tumor bearing 
animals. This demonstrates that BMX-001 has differential effects in tumor tissue compared to 
normal tissues, with BMX-001 showing potential to protect normal tissues and sensitize tumors 
to RT. Thus, the rationale for this protocol is based on the demonstrated dual activity of BMX-
001 to protect normal tissue while sensitizing tumors to therapy [19]. 
Preclinical safety toxicology studies have shown a No Observable Effect Level (NOEL) in mice of 
12 mg/kg and in cynomolgus monkeys of 2 mg/kg. BioMimetix has concluded a Phase 1 dose 
escalation study in newly diagnosed high-grade glioma patients. This clinical trial has 
demonstrated no adverse effects in subcutaneous dosing up to 28 mg/subject load with half the 
loading dose given biweekly for 8 weeks in 12 subjects. Three subjects were enrolled and dosed 
with 42 mg/subject load with half the loading dose given biweekly for 8 weeks. Of these three 
subjects, there was one dose-limiting toxicity of grade 3 tachycardia and grade 3 hypotension. 
The DLT in this subject occurred with the loading dose (42 mg sc). The patient was treated with 
fluids and hospital admitted for observation for 24 hours during which time the hypotension and 
tachycardia resolved. The cardiac rhythm was a sinus tachycardia and no other cardiac toxicity 
was observed. The tachycardia was assumed to have resulted from hypotension occurring 
following the sub-cutaneous injection of BMX-001 (42 mg). After the loading dose of BMX-001 
and the described DLT, the subject continued on study and experienced no tachycardia or 
hypotension following administration of the subsequent 16 maintenance doses (20 mg sc).  
The most common related toxicity see in this Phase 1 trial was injection site reaction and all of 
these have been grade 1. There is no apparent toxicity to end organ tissues or bone marrow. 
The completion of a Phase 1 clinical trial in patients with high-grade glioma undergoing brain 
radiation therapy plus chemotherapy with temozolomide has established an MTD for BMX-001. 
The MTD by sub-cutaneous injection is 28 mg/subject load followed by a maintenance dose of 14 
mg/subject b.i.w. At the MTD, there have been no BMX-001 dose limiting toxicities observed.  
Based on the completion of Phase 1 and establishment of an MTD for this treatment regimen in 
patients undergoing radiation therapy and chemotherapy, this clinical trial of head and neck 
cancer patients will proceed to a Phase 2 trial of 48 subjects with a safety lead-in of 6 subjects. 
The reason for the safety lead-in is to confirm safety in subjects receiving radiation therapy to the 
head and neck area and with chemotherapy involving cisplatin. 
4.3 
Study Design 
This study will involve escalating doses of BMX-001 with standard of care concurrent RT and 
cisplatin. Patients with biopsy-proven head and neck cancer (squamous cell carcinoma) will 
undergo standard staging consisting of history and physical exam, contrast enhanced CT +/- PET 
scan and/or MRI, and QoL questionnaires. Intensity modulated radiotherapy (IMRT) will be 
delivered with once daily 2.0-2.1 Gy fractions for definitive intent or adjuvant post-operative 
patients requiring chemo-radiation for high-risk disease including evidence of positive margins 
or extracapsular lymph node extension. Patients undergoing definitive intent IMRT will receive 
69.3-70 Gy in 33 -35 fractions. Post-operative IMRT will be delivered to a dose range of 60-66 Gy 
in 30-33 fractions. 
Cisplatin will be delivered per investigator choice, either 100 mg/m2 IV q21 days x 2, 100 mg/m2 
IV q21 days x 3, or 30-40 mg/m2 IV weekly x 6-7 doses. All of these dosing schedules are 


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acceptable as standard of care per NCCN guidelines and utilized within NCI-sponsored 
cooperative groups [29]. A minimum of 3 subjects and a maximum of 54 subjects with locally 
advanced head and neck cancers will be enrolled into this study during a 48-month period. 
4.3.1 
Phase 1- Completed 
We have conducted a dose-escalation study of BMX-001 in combination with standard dose 
intensity modulated radiation therapy (IMRT) and concurrent cisplatin (CRT) to determine the 
safety of the investigational drug, BMX-001 with concurrent cisplatin and radiation therapy. 
Since a RP2D of 28 mg/subject load/14 mg/subject maintenance (Dose Level 3) has recently 
been confirmed in a Phase 1 trial of BMX-001 (with Temozolomide for chemotherapy and brain 
radiation as opposed to the cisplatin and head/neck radiation to be completed in this trial). This 
Phase 1 trial in head and neck cancer patients was only completed through Dose Levels 1 and 2. 
Patients with locally advanced (stage III-IVB) HNSCC for whom radiation plus cisplatin is 
appropriate were eligible based on inclusion and exclusion criteria. Subjects were administered 
BMX-001 subcutaneously as a loading dose on day -4 to 0. Starting on day 1 or 2 of CRT patients 
received a maintenance dose (50% of loading dose) twice weekly administered on days of 
radiation therapy and for one week after radiation concluded. Cisplatin was administered per 
institution’s standard of care practice. Common standard of care practice includes dosing 
cisplatin at 100mg/m2 IV q21 days starting on Day 1 of RT for 2-3 doses or dosing cisplatin at 30-
40 mg/m2 IV on Monday or Tuesday of each week of RT for 6-7 total doses. Patients received a 
continuous course of IMRT delivered as single daily fractions of 2.0 -2.1 Gy with a cumulative 
radiation dose between 60 Gy and 70 Gy depending on whether they have undergone resection 
or are receiving definitive radiation therapy. Planned radiation treatment volumes included at 
least two oral sites (buccal mucosa, floor of mouth, oral tongue, soft palate, hard palate, 
retromolar trigone) with each site receiving a minimum total of 50 Gy. 
In order to evaluate the pharmacokinetics (PK) of BMX-001, blood samples were drawn for 
analysis.   
Cohorts of 3 subjects have been accrued with dose escalation, beginning with 7 mg/subject load 
and ending with 14 mg/subject load. Following the treatment of 3 subjects at dose levels 1 and 
2, and with no BMX-001 related dose limiting toxicities as defined in this protocol, the Phase 1 
portion is completed. 
4.3.2 
Phase 2 
We will do a safety lead-in trial for head and neck cancer patients involving 6 subjects at the 28 
mg/subject loading dose given by subcutaneous injection followed by one-half the loading dose 
(14mg/subject) administered by subcutaneous injection biweekly during the remainder of the 
trial. We will assess safety in a lead-in cohort of 6 head and neck cancer patients being treated 
with cisplatin and radiation therapy.  Once those 6 subjects are enrolled, we will then move to full 
Phase 2 open enrollment. Based on the preclinical safety toxicology studies in mice and monkey 
and the results of the Phase 1 BMX-001 high-grade glioma trial in humans, we anticipate that a 
dose of 28 mg/subject load followed by one-half the loading dose (14 mgs) twice weekly will not 
have dose-limiting toxicities in patients enrolled in this study. If this expectation is confirmed 
(meaning there are no definite BMX-001-related dose-limiting toxicities, defined as grade 3 study-
drug-related adverse events), this dose will be utilized in the full Phase 2 trial enrolling an 
additional 42 subjects. If one or more definite BMX-001 related grade 4 or 5 DLTs occur in the 6 
patient safety lead-in cohort, accrual will pause pending review by the sponsor and DSMB. Non 


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BMX-001 related DLTs are anticipated in this patient population due to the primary disease and 
treatment regimen. 
This is not a randomized trial. All eligible patients enrolled will receive BMX-001. 
A maximum of 48 patients will be enrolled in this Phase 2 clinical trial. 
4.4 
Rationale 
4.4.1 
Study Rationale 
Patients undergoing CRT, typically with cisplatin-based regimens, can experience incapacitating 
acute and chronic functional disabilities in the form of dry mouth, loss of taste, mucositis or 
breakdown of the mucosal lining within the head and neck area, swallowing problems 
(dysphagia and odynophagia), and radiation dermatitis that can result in fibrosis and scarring of 
the skin and subcutaneous tissue. BMX-001 added to RT and cisplatin has the potential not only 
to benefit the survival of HN patients through improved tumor control but also to protect 
against the development of these types of toxicities and to prevent impairment of QoL. 
Therefore, we have started by performing a Phase 1 trial of BMX-001 at escalating doses in 
combination with standard RT, 30-35 daily fractions to 60-70 Gy, plus cisplatin at the standard of 
care dosing, which could be either dosing at 30-40 mg/m2 administered IV once per week for 6-7 
weeks or 100 mg/m2 days 1 of RT and repeated q21 days for either 2 or 3 total doses. Cisplatin 
administration will be at the discretion of the treating team. Both regimens are considered 
acceptable standards within radiation oncologist-led cooperative groups such as the NRG. We 
hypothesize that BMX-001, when added to standard RT and cisplatin, will be safe at 
pharmacologically relevant doses in patients undergoing concurrent CRT for head and neck 
cancers. Since safety has been determined both in Dose Level 1 and Dose Level 2 for the Phase 1 
portion of this study and for Dose Levels 1-3 in a separate Phase 1 safety study in patients with 
high-grade glioma, with establishment of an MTD, we will move to a Phase 2 expansion cohort 
to further study the safety and examine the effects of BMX-001 in combination with concurrent 
chemoradiation in the amelioration of mucositis, xerostomia, and radiation dermatitis in 
patients with stage III-IVb HNSCC.  
4.4.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
The recommended doses of BMX-001 are based on preclinical safety studies done in rats, mice, 
guinea pigs, dogs, and baboons, and the results of a completed Phase 1 trial in human subjects. 
4.5 
Quality of Life and Function Assessments 
Before and during treatment for head and neck cancer, adult patients experience a decline in 
perceived HRQoL [30-35]. Liu defines HRQoL as “a concept that encompasses the multi-
dimensional well-being of a person and reflects an individual’s overall satisfaction with life.” 
[31].  
In order to capture fully the many aspects of HRQoL, we will utilize both objective and subjective 
measures to evaluate issues with fatigue and HRQoL. Subjectively, HRQoL is measured using 
patient-reported outcome questionnaires known as patient-reported outcomes (PROs). Four 
PROs will be used to assess functional status, self-reported measures of mucositis, self-reported 
measures of xerostomia, and self-reported measures of skin rash and discomfort: Functional 
Assessment of Cancer Therapy-Head & Neck (Version 4) (FACT-HN), Oral Mucositis Weekly 
Questinaire-Head+Neck (OMWQ-HN), Xerostomia-Related Quality of Life Scale (XeQoLS), and 


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Dermatology Life Quality Index (DLQI). The FACT-HN and first two questions of the OMWQ-HN 
measure overall HRQoL, which is the effect of disease and treatment on overall well-being. The 
remaining questionnaires are symptom or functional assessments. It has been shown that 
symptom and functional assessments provide necessary detailed information of the symptom 
burden on the patient that general measures of HRQoL are not sensitive enough to detect [36]. 
This data has also been shown to correlate poorly with toxicity scoring in some instances [37], 
making this information an important addition to the evaluation of treatment on well-being.  
The FACT-HN version 4 is a multidimensional, self-report QoL instrument specifically designed 
for use with head and neck cancer patients (see Appendix B). It consists of 27 core items which 
assess patient function in four domains: Physical (Cronbach’s α = .79), Social/Family (α = .59), 
Emotional (α = .59), and Functional Well-Being (α = .75), which is further supplemented by 12 
site-specific items to assess for head and neck-related symptoms (α = .63). The first four 
domains can be combined for a general assessment of function (FACT-G; α = .89) [38]. Each item 
is rated on a 0 to 4 Likert type scale and then combined to produce subscale scores for each 
domain, as well as a global QoL score. Higher scores represent better QoL [39]. The FACT-HN can 
be completed by the patient or by an interview and has an effect size of .55 [21]. The scale’s 
sensitivity and ability to differentiate between known groups was tested by comparing the scale 
to Karnofsky performance status (low KPS < 80, high KPS > 80) and treatment status (on 
treatment vs. off treatment for greater than 3 months) and all domains were able to distiguish 
between good and poor performance at the p < .0001 level, except the emotional domain, p = 
.08 [38]. The data also showed that 2-3 point differences on subscales appeared clinically 
meaningful. To determine convergent and discriminant validity, the FACT-HN was correlated 
with the Performance Status Scale for Head and Neck (PSS-HN), which includes 3 domains: 
normalcy of diet, understandability of speech, and eating in public [38]. As expected, the three 
scales of the PSS-HN were significantly correlated with the head and neck subsection of the 
FACT-HN (Spearman’s r = 0.66, p < 0.0001; r = 0.17, p < .05; r = 0.42, p < 0.0001, respectively). 
Both diet and eating in public were also correlated with FACT-G (r = .24, p < .005; r = .20, p < 
.05). At least one construct from the PSS-HN was not correlated with each of the remaining 
constructs in the FACT-HN.  
The OMWQ-HN is a 13 item functional assessment of mucositis using a Likert response format 
(See Appendix C). The items were developed by qualitative data provided by one on one 
interviews with 30 head and neck cancer patients [39]. Based on these results, questions were 
modified to ensure the scale was comprehensive, that there were no irrelevant questions, and 
for clarity of all items. The first two questions assess overall health and overall quality of life on a 
7-point Likert scale. The third question quantifies overall mouth and throat soreness on a 5-
point scale. The next six questions assess how much mouth and throat soreness limits certain 
activities on a 5-point scale. The last three questions further assess the degree of mouth and 
throat pain and soreness using an 11-point scale (overall Chronbach’s α = .91). All items 
correlated strongly (Spearman’s r’s > .7) except the overall health and overall QoL items and the 
brushing teeth item (r < .5). Therefore these items are not calculated into the overall OMWQ-HN 
score. 
To evaluate validity, the OMWQ-HN was given at four timepoints with the FACT-HN and PSS-HN 
to 75 patients with HNC who were receiving radiotherapy with or without chemotherapy [40]. 
The OMWQ-HN and the FACT-HN were significantly correlated (η = −0.57), however the OMWQ-
HN and the PSS-HN were not as strongly correlated (η range = −0.09 to −0.37), suggesting that 


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syptoms from mucositis do not readily overlap with normalcy of diet, understandability of 
speech, and eating in public. Three levels of pain were assessed by a Likert scale which stated “I 
have pain” and had three response options: not at all/a little bit, somewhat, and quite a bit/very 
much. There was a significant difference in scores on the OMWQ-HN depending on this variable, 
F(2.62) = 38.6, p < .001, ES = .77-.99. There was also significant divergence between patients 
who used opioid analgesics compared to those who did not, such that those who were using 
analgesics scored worse (p = .002, ES = 0.87). Timepoints were 24-48 hours apart, providing a 
test-retest correlation of .89. Sensitivity to change was shown by determining changes in the 
pain item and normalcy of diet item to compare OMWQ-HN scores between no change/
improved groups and worsened groups, t(63) = -4.3, p < .001, and t(63) = -2.6, p =.013, 
respectively. It has also been shown that the OMWQ-HN is more responsive than less symptom-
focused QoL instruments in detecting early changes in symptoms related to oral mucositis [40].  
The subjective impact of salivary gland dysfunction and xerostomia is assessed by collecting 
stimulated and unstimulated saliva production (See Section 13.1.6) and by using the 
Xerostomia-Related Quality of Life Scale (XeQoLS) developed at the University of Michigan 
(Appendix D). In its first form, the XeQoLS contained 8 questions developed through literature 
reviews, patient surveys, and the input of oncologists specializing in head and neck cancer, and 
was shown to parallel clinically measured salivary gland function [40-42]. Research showing that 
there were four domains to oral health-related quality of life led to the current 15 item scale 
that covers physical functioning (Cronbach’s α = .85), personal/psychological functioning (α = 
.87), social functioning (α = .86), and pain/discomfort issues (α = .89). The Cronbach alpha 
coefficient for the total XeQoLS score was also significant (α = .96, p < 0.001) [43]. Internal 
validity was assessed by comparing the 15 item xeQoLS to the previous 8 item version (α = .36 to 
.73, p < 0.001). Correlations were significant between the scale and salivary flow (r =−.19 to 
−.28, p < .05) and there were expected between group differences when comparing those who 
had parotid-sparing radiotherapy compared to those that did not such that parotid-sparing 
provides better XeQoL [43].  
The Dermatology Quality of Life Index (DLQI) is a well established 10 item questionnaire used to 
assess impacts of skin irritation on patients well-being and functionality (Appendix E). Although 
the DLQI was first developed to treat disorders of the skin, it has been validated in over 30 
different skin dysfunctions and has been shown to be a valid measure for erythema, inflam-
mation, atopic eczema, and pruritus. It is currently being used to assess radiation-induced 
damage in two large head and neck cancer studies, including RTOG 0920 [44,45]. The DLQI 
consists of 10 items and covers 6 domains including symptoms and feelings, daily activities, 
leisure, work and school, personal relationships, and treatment. Scores are on a 4-point Likert 
scale from “not at all,” to “very much,” and each has an option of “not relevant,” with higher 
scores indicating worse HRQoL. Score differences of 4 points have been shown to be statistically 
significant [46-50]. The scale was shown to distinguish between pre-emptive treatment vs. 
reactive treatment to radiation-induced skin toxicities in a colorectal cancer patient population 
[51]. 


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5 
Objectives 
5.1 
Phase 1 
5.1.1 
Primary Objective 
To determine the safety and toxicity profile of BMX-001 in conjunction with RT and concurrent 
cisplatin chemotherapy for patients with locally advanced head and neck cancers. 
5.1.2 
Secondary Objectives 
1) To assess the effect of BMX-001 in combination with RT and concurrent cisplatin in 
newly diagnosed HNSCC patients on overall survival (OS), progression free survival 
(PFS), and initial response to treatment. 
2) To examine the impact on mucositis of BMX-001 in combination with RT and 
concurrent cisplatin in treatment of newly diagnosed patients with locally advanced 
head and neck cancers by evaluating the degree of oral mucositis at 30-39 Gy, 40-49 
Gy, 50-59 Gy, and 60-70 Gy, the duration of oral mucositis, and evaluation of 
mucositis-related patient-reported outcomes. 
3) To examine the impact on xerostomia of BMX-001 in combination with RT and 
concurrent cisplatin by evaluating degree of xerostomia at 30-39 Gy, 40-49 Gy, 50-
59 Gy, and 60-70 Gy, the duration of xerostomia, and evaluation of xerostomia-
related patient-reported outcomes. 
4) To examine the impact on radiation dermatitis of BMX-001 in combination with RT 
and concurrent cisplatin at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the 
duration of radiation dermatitis, and evaluation of radiation dermatitis-related 
patient-reported outcomes 
5) To characterize the single-dose and repeated-dose pharmacokinetic profiles of 
BMX-001 when delivered in combination with RT and concurrent cisplatin. 
5.1.3 
Exploratory Objective 
1) To describe patient-reported outcomes of health-related quality of life (HRQoL) in 
HNSCC patients treated with BMX-001 in combination with RT and concurrent 
cisplatin. 
5.2 
Phase 2 Endpoints 
 
2) The primary endpoint is incidence of severe oral mucositis (grade 3 and 4). 
3) The secondary endpoints are: 
1. Median duration (days) of severe oral mucositis) 
2. Median time (days) to onset of severe oral mucositis 
3. Incidence of grade >/= 2 Xerostomia at month 1 and 6 post completion 
of RT. 
5.3 
Phase 2 Objectives 
1) To confirm the safety and tolerability of the MTD of BMX-001 in conjunction with RT 
and concurrent cisplatin in a cohort of newly diagnosed patients with locally 
advanced head and neck cancers. 


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2) To further explore efficacy based on the impact of BMX-001 on mucositis, 
xerostomia, and radiation dermatitis in treatment of newly diagnosed patients with 
locally advanced head and neck cancers by evaluating the degree of these adverse 
events at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of the adverse 
events, and evaluation of related patient-reported outcomes. 
 
5.3.1 
Secondary Objective 
1) To assess the efficacy of BMX-001 at the MTD in a cohort of HNSCC patients based 
upon overall survival (OS), median progression free survival (PFS), and initial 
response to treatment. 
2) To assess radiographic response in locally advanced HNSCC patients treated with 
standard RT and cisplatin with BMX-001 at the MTD. 
5.3.2 
Exploratory Objectives 
3) To further describe patient-reported outcomes of HRQoL in locally advanced HNSCC 
with standard RT, cisplatin, and BMX-001 at the MTD.  


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6 
Patient Selection 
6.1 
Inclusion Criteria 
1) Pathologically confirmed (histologically or cytologically) diagnosis of squamous cell 
carcinoma of the oropharynx, larynx, hypopharynx, nasopharyngeal, or oral cavity 
with clinical or pathologic high-risk features for whom cisplatin and radiation would 
be considered appropriate care. 
2) Treatment plan to receive a continuous course of IMRT delivered as single daily 
fractions of 2.0 to 2.1 Gy with a cumulative radiation dose between 60 Gy and 70 Gy 
depending on whether patients are considered post-operative high risk or 
unresectable/organ preservation high risk. Planned radiation treatment fields must 
include at least two oral sites buccal mucosa, retromolar trigone, floor of mouth, 
oral tongue, soft palate, hard palate) with a portion of each site receiving a 
minimum total of 50 Gy. 
3) Patients who are to undergo definitive chemoradiation must have clinically or 
radiographically evident measurable disease at the primary site and/or at nodal 
stations. Tonsillectomy or local excision of the primary without removal of nodal 
disease is permitted, as is excision removing gross nodal disease but with intact 
primary site. 
4) Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-
therapeutic nodal excisions. Fine needle aspirations of the neck that are positive for 
squamous cell carcinoma are sufficient for diagnosis pending pathology review at 
participating institutions. 
5) For patients undergoing curative intent resection the following criteria are required: 
• 
Pathologically (histologically or cytologically) proven diagnosis of head and 
neck squamous cell carcinoma 
• 
Patients must have undergone gross total surgical resection within 42 days 
prior to registration and beginning of therapy under the clinical trial. Note: 
Patients may have biopsy under general anesthesia in an operating room 
followed by definitive ablative cancer surgery representing gross total 
resection. 
6) Clinical or pathologic stage Stage III-IVB per AJCC, 7th edition. 
7) General history and physical examination by a radiation oncologist and medical 
oncologist within 4 weeks prior to enrollment. 
8) Examination by an ENT or head and neck surgeon, including laryngopharyngoscopy 
(mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to 
enrollment. 
9) Axial imaging of the neck and chest- CT, MRI and/or PET/CT is acceptable, within 8 
weeks prior to date of consent. 
10) Age ≥ 18 years. 
11) Zubrod Performance Status 0-2 within 4 weeks prior to enrollment. 
12) CBC/differential obtained within 2 weeks prior to starting the study drug with 
adequate bone marrow function, defined as follows: 
• 
Hemoglobin ≥ 9.0 g/dl;  
• 
Platelets ≥ 100,000 cells/mm3; 
• 
Absolute neutrophil count (ANC) > 1,500 cell/mm3. 


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13) Adequate hepatic function as defined as follows: 
• 
Total bilirubin < 2x institutional ULN within 2 weeks prior to starting the 
study drug;  
• 
AST and ALT <3x institutional ULN within 2 weeks prior to starting the study 
drug.  
14) Adequate renal function defined as follows: 
• 
Serum creatinine < 1.5 mg/dl within 2 weeks prior to starting the study drug 
or creatinine clearance rate (CCr) ≥ 50 mL/min within 2 weeks prior to 
starting the study drug determined by 24-hour collection or estimated by 
Cockcroft-Gault formula: 
o CCr male = [(140 – age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] 
o CCr female = 0.85 x (CrCl male) 
15) Patient must be willing and able to follow study procedures and instructions. 
16) Patient must provide study-specific informed consent within 28 days prior to 
starting the study drug. 
17) Negative pregnancy test for women of child-bearing potential within 48 hours prior 
to first dose of BMX-001. 
18) Women of childbearing potential and male participants must agree to use a 
medically effective means of birth control throughout their participation in the 
treatment phase of the study and until 12 months following the last study 
treatment. 
6.2 
Conditions for Patient Ineligibility (Exclusion Criteria) 
1) Stage I or II; T1N1 and T2N1 stage III presentations per AJCC 7th edition 
2) Distant metastasis  
3) Hypertension requiring 3 or more anti-hypertensive medications to control  
4) Grade ≥2 hypotension at screening 
5) 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 
6) History of syncope within the last 6 months 
7) Patients receiving, or unable to stop use at least 1 week prior to receiving the first 
dose of BMX-001, medications listed in Section 12.2 of the protocol are not eligible. 
8) Pregnancy or women of childbearing potential and men who are sexually active and 
not willing/able to use medically acceptable forms of contraception; this exclusion is 
necessary because the treatment involved in this study may be significantly 
teratogenic 
9) Women who are breast feeding are not eligible 
10) Prior allergic reaction to cisplatin 
11) Known hypersensitivity to compounds of similar chemical composition to BMX-001 
12) Grade 3-4 electrolyte abnormalities (CTCAE v 4.03) except sodium, which must be 
≥126 mmol/L. 
13) Prior unrelated malignancy requiring current active treatment with the exception of 
cervical carcinoma in situ, basal cell carcinoma of the skin, resected T1-2N0M0 
differentiated thyroid cancers, invasive cancers with a 3-year disease-free interval, 
Ta bladder cancers, or low and favorable intermediate risk prostate cancer. 
14) Prior history of HNSCC receiving radiation or chemo-radiation. 


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15) Prior systemic chemotherapy for the study cancer (including neoadjuvant 
chemotherapy); note that prior chemotherapy for a different cancer is allowable. 
16) Prior radiotherapy that would result in overlap of radiation treatment fields with 
planned treatment for study cancer. 
17) A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of 
a QTc interval >480 milliseconds (ms) (CTCAE grade 1) using the specific/usual 
choice by clinical center for correction factor. 
18) A history of additional risk factors for Torsades de Pointes (e.g., congestive heart 
failure, hypokalemia, known family history of Long QT Syndrome). 
19) Severe, active co-morbidity, defined as follows: 
• 
Cardiovascular disease or cerebrovascular disease, for example 
cerebrovascular accidents or myocardial infarction ≤ 6 months prior to study 
enrollment, unstable angina, New York Heart Association (NYHA) Grade II or 
greater congestive heart failure (CHF), or serious cardiac arrhythmia 
uncontrolled by medication or with the potential to interfere with protocol 
treatment; 
• 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or 
recent arterial thrombosis) within 6 months prior to enrollment; 
• 
History or evidence upon physical/neurological examination of central 
nervous system disease (e.g., seizures) unrelated to cancer unless 
adequately controlled by medication;  
• 
Acute bacterial or fungal infection requiring intravenous antibiotics within 7 
days of enrollment; 
• 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy within 30 days 
of registration; 
• 
Patients known to be HIV positive or have active viral hepatitis.  


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7 
Pretreatment Evaluations/Management 
7.1 
Informed Consent 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other 
study-related matters. This discussion will occur in a location that ensures subject privacy and in 
a manner that minimizes the possibility of coercion. Appropriate accommodations will be made 
available for potential subjects who cannot read or understand English or are visually impaired. 
Potential subjects will have the opportunity to contact the Principal Investigator or authorized 
key personnel with questions and will be given as much time as needed to make an informed 
decision about participation in the study. 
Before conducting any study-specific procedures, the Principal Investigator or delegate must 
obtain written informed consent from the subject or a legally authorized representative. The 
original informed consent form will be stored with the subject’s study records, and a copy of the 
informed consent will be provided to the subject. The Principal Investigator or delegate is 
responsible for asking the subject whether the subject wishes to notify his/her primary care 
physician about participation in the study. If the subject agrees to such notification, the Principal 
Investigator or delegate will inform the subject’s primary care physician about the subject’s 
participation in the clinical study. 
7.2 
Screening Examination 
The screening examination will take place within 21 days prior to starting BMX-001. The 
screening evaluation and baseline evaluation may be combined. Standard of Care assessments 
(such as performance status, labs and imaging) completed per inclusion and exclusion criteria 
but prior to signing ICF may be utilized for eligibility purposes. An informed consent must be 
signed by the patient before any screening procedures take place. Subject data to be collected 
at the Screening Examination includes physical examination, vital signs, height (may be done at 
baseline), weight, laboratory studies (complete blood count with differential, complete 
metabolic panel and PT/aPTT), past medical history, and concomitant medications. Mucositis 
assessment will be done at the screening visit. Assessment of measurable disease by imaging 
will be done per standard of practice at each institution. 
Physical, vital signs (temperature, respiratory rate, blood pressure, and pulse), height (done 
once at screening or baseline), weight, ECG, and mucositis must be performed at baseline 
(Day -4 to 0). Saliva production and questionnaires will also be done at baseline. Serum beta-
HCG is measured on women of childbearing potential no more than 48 hours prior to the first 
dose of BMX-001. 


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8 
Registration Procedures and Administrative Considerations 
8.1 
Enrollment Procedure  
Once an Investigator at a participating center has verified that eligibility criteria have been met 
and the case has been discussed with the participating Principal Investigator, the patient is 
enrolled in the study. 
8.2 
Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations. 
8.3 
Institutional Review Board and Protocol Review 
Western IRB (WIRB) will be the primary IRB for this study. The protocol, informed consent form, 
advertising material, and additional protocol-related documents must be submitted to the IRB 
for review. Additional protocol review committees and/or scientific review committees may be 
used per institutional protocol. The Principal Investigator will follow each institution’s policies 
and procedures as required to ensure activity of the protocol.  
8.4 
Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s 
data will be maintained.  
To protect privacy, every reasonable effort will be made to prevent undue access to subject’s 
personal information during the course of the study. Prospective participants will be consented 
in an exam room where it is just the research staff, the patient and family, if desired. For all 
future visits, interactions with research staff (study doctor and study coordinators) regarding 
research activities will take place in a private exam room. All research-related interactions with 
the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
To protect confidentiality, subject files in paper format will be stored in secure locations 
accessible only by the research staff. Subjects will be identified only by a unique study number 
and subject initials. Electronic records of subject data will be maintained in encrypted and 
password-protected files, which are maintained on a dedicated, HIPAA-compliant server and 
accessed through a secure network. Access to the electronic database will be limited to the 
Principal Investigator, sub-investigators, study coordinators, the statistical team, the clinical trial 
monitors, the data management team including the clinical trial manager, and the sponsor. 
Record of any changes to the electronic database will be maintained and included in the audit 
trail. 
Upon completion of the study, research records will be archived and handled per local 
institutional policy. Subject names or identifiers will not be used in reports, presentations at 
scientific meetings or publications in scientific journals. 
8.5 
Protocol Amendments 
All protocol amendments must be initiated by the sponsor or Principal Investigator at each 
participating institution and approved by the IRB prior to implementation. IRB approval is not 


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required for protocol changes that occur to protect the safety of a subject from an immediate 
hazard. However, the Principal Investigator must inform the IRB and all other applicable 
regulatory agencies of such action immediately. 
8.6 
Conflict of Interest 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and 
local regulations regarding reporting, and disclosure of conflict of interest. Conflicts of interest 
may arise from situations in which financial or other personal considerations have the potential 
to compromise or bias professional judgment and objectivity. Conflicts of interest include but 
are not limited to royalty or consulting fees, speaking honoraria, advisory board appointments, 
publicly-traded or privately-held equities, stock options, intellectual property, and gifts. 
Local regulatory authorities will review and manage research-related conflicts of interest. The 
Principal Investigator and Sub-Investigators must report conflicts of interest annually and, when 
applicable, must have a documented management plan that is developed in conjunction with 
the local office and approved by the IRB/Institutional Ethics Committee (IEC). 


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9 
Radiation Therapy  
NOTE: FOR THIS STUDY, IMRT OR VMAT IS MANDATORY. (IGRT is required; however, margin 
reduction is not permitted even when IGRT is used). 
Treatment plan should include a continuous course of IMRT delivered as single daily fractions of 
2.0 to 2.1 Gy with a cumulative radiation dose between 60 Gy and 70 Gy. Planned radiation 
treatment volumes must include at least two oral mucosal sub-sites (buccal mucosa, retromolar 
trigone, floor of mouth, tongue, soft palate, hard palate) with a portion of each site receiving at 
least 50 Gy. 
For post-operative irradiation, the standard of care is that radiation therapy will not be initiated 
until good wound healing has been achieved and will be initiated no earlier than 28 days 
following surgical resection of the malignancy. 
9.1 
Dose Specification For Clinically Measurable Disease 
IMRT will be delivered in 30-35 fractions over 6 weeks, 5 fractions weekly in one plan (SIB) or 35 
fractions over 7 weeks, 5 fractions weekly using sequential plans. Concomitant boost using 
separate IMRT plans is not allowed. 
For Patients Treated with SIB Technique 
Missed treatments due to holidays or logistic reasons can be compensated for by delivering an 
additional BID treatment during the week, OR treating on the Saturday or Sunday of that week, 
OR adding to the end of treatment. 
The primary tumor and involved nodes (CTV1) will typically consist of a 0.5-1.5 cm expansion of 
the gross tumor volume (GTV) to cover potential local invasion and will be prescribed 2 Gy/
fraction, total 70 Gy. 
High-risk sub-clinical disease sites, which include possible local subclinical infiltration at the 
primary site (primary site CTV2) and first echelon nodes, which are not clinically or 
radiographically involved (nodal CTV2), should be expanded by 3-5 mm to create PTV2. PTV2 
should receive 1.6 Gy/fraction to a total dose of 56 Gy. 
Lower-risk targets (PTV3) (such as neck nodal levels which are not first echelon nodes and are 
not adjacent to levels containing grossly involved nodes) will be prescribed 50-52.5 Gy (at 1.43-
1.5 Gy/fraction, BED2 = approximately 40-45 Gy). 
Non-uniform or larger expansions to encompass high-risk anatomical compartments may be 
necessary. 
Either of two options is acceptable for treatment of the low neck. One option is to treat with 
isocentric matching AP or AP-PA fields with larynx block, matched to the inferior margin of the 
IMRT portals just above the arytenoids. The dose will be 2 Gy per fraction prescribed to 3 cm 
depth to a total dose of 44 Gy in 22 daily fractions. Whole-neck IMRT is also allowed as an 
alternative approach. Involved low neck nodes will receive at least 60 Gy in 30 fractions. This can 
be achieved by either boosting the low neck field with an additional 16 Gy in 8 fractions, by an 
AP or AP-PA fields, or by planning the whole neck using IMRT. In cases of gross involvement of 


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the vallecula or low neck, whole-neck IMRT should be considered. Whole-neck IMRT may be 
preferable if level VI is considered to be at risk due to gross involvement of level IV nodes. 
For Patients Treated with Sequential Plans Technique 
Missed treatments due to holidays or logistic reasons can be compensated for by delivering an 
additional BID treatment during the week, OR treating on the Saturday or Sunday of that week, 
OR adding to the end of treatment. 
The primary tumor and involved nodes (CTV1) will typically consist of a 0.5-1.5 cm expansion of 
the gross tumor volume (GTV) to cover potential local invasion and will be prescribed 2 Gy/
fraction, total 70 Gy. Non-uniform or larger expansions to encompass high-risk anatomical 
compartments may be necessary. 
High-risk subclinical disease sites, which include possible local subclinical infiltration at the 
primary site (primary site CTV2) and first echelon nodes, which are not clinically or 
radiographically involved (nodal CTV2), should be expanded by 3-5 mm to create PTV2. PTV2 
should receive 2 Gy/fraction to a total dose of 60 Gy.  
Lower-risk targets (PTV3) (such as neck nodal levels which are not first echelon nodes and are 
not adjacent to levels containing grossly involved nodes) should receive 44 Gy in 2 Gy fractions. 
Either of two options is acceptable for treatment of the low neck. One option is to treat with 
isocentric matching AP or AP-PA fields with larynx block, matched to the inferior margin of the 
IMRT portals just above the arytenoids. The dose will be 2 Gy per fraction prescribed to 3 cm 
depth to a total dose of 44 Gy in 22 daily fractions. Whole-neck IMRT is also allowed as an 
alternative approach. Involved low neck nodes will receive at least 60 Gy in 30 fractions. This can 
be achieved by either boosting the low neck field with an additional 16 Gy in 8 fractions, by an 
AP or AP-PA fields, or by planning the whole neck using IMRT. In cases of gross involvement of 
the vallecula or low neck, whole-neck IMRT should be considered. Whole-neck IMRT may be 
preferable if level VI is considered to be at risk due to gross involvement of level IV nodes. 
All plans must be normalized such that 95% of the volume of the PTV1 is covered with 
prescription dose of 70 Gy. Additionally: 
• 
At 1 cc PTV1 volume on the DVH curve, the dose should not be > 110% of the prescribed 
dose. 
• 
At a volume of 0.03 cc within the PTV1 volume on the DVH curve, the dose should not 
be < 95% of the prescribed dose. 
• 
For any volume of tissue outside the PTVs that has a size of 1 cc, the dose should not be 
> 74 Gy for definitive radiation. 
• 
For Resected Patients the prescribed radiotherapy dose will be 60 - 66 Gy in 2 Gy once-
daily fraction size (total of 30-33 fractions) Radiotherapy should begin on a Monday, 
Tuesday or Wednesday. The daily dose of 2 Gy will be prescribed such that 95% of the 
PTV60 volume receives at least 60 Gy. PTV56 is also used, and PTV66 (given as an 
integrated boost) may be optionally defined. Three-dimensional conformal radiotherapy 
followed by a 6 Gy boost is not permitted.  


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9.2 
Technical Factors 
9.2.1 
Treatment Planning/Delivery 
Megavoltage energy photon beam (6 MV preferred) irradiation is required. 
9.2.2 
Image Guidance for IGRT 
Image guidance of IMRT may be achieved using any one or more of the following techniques: 
• 
Orthogonal kilovoltage (KV) images, e.g., kVOBI, ExacTrac; 
• 
Linear-accelerator mounted kV and MV helical conebeam CT images; 
• 
Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
9.3 
Localization, Simulation, and Immobilization 
Patients must have an immobilization device (e.g., Aquaplast Orfit mask) made prior to 
treatment planning CT scan. 
The treatment planning CT scan should be performed ideally with IV contrast so that the major 
vessels of the neck are easily visualized and to optimally visualize the tumor. The treatment 
planning CT scan must be performed with the immobilization device and in the treatment 
position. Slice thickness should be no greater than 0.3 cm. 
Image guidance and verification should be performed at least twice weekly and more frequently 
if clinically indicated. 
9.4 
Treatment Planning/Target Volumes 
9.4.1 
Definition of Target Volumes for Unresected Patients (Who Receive Definitive 
Chemoradiation) 
Planning Target Volumes (PTVs): In general, the PTV should not go outside of the skin surface; if 
it does exceed the skin surface, the application of bolus material over this portion of the PTV 
may be considered if it is judged clinically that the skin is at risk but is generally not 
recommended. 
• 
PTV expansion with credentialing for daily IGRT: For those institutions that are using 
IGRT for margin reduction, the minimum CTV-to-PTV expansion is 3.0 mm (a larger 
expansion may be necessary for a target volume subject to significant intrafraction 
variability, such as the non-immobilized oral tongue). In general, the CTV-to-PTV 
expansion (with IGRT) should not exceed 5 mm. 
• 
IMRT Dose Prescription to PTVs for the Unresected Patient: The goal is for 95% of the 
PTV70 to receive ≥ 2 Gy with a minimum dose (cold spot) of no less than 66.5 Gy. It is 
recognized that portions of the PTV70 close to the skin may receive significantly less 
than 66.5 Gy. This is acceptable as long as cold spots within PTV1 do not exist at a depth 
deeper than 8 mm beneath the skin. 
For planning prioritization and priorities in dose coverage, in the final plan, PTV1 will be the 
highest priority target structure. PTV2 and PTV3, if applicable, will be ranked in the IMRT 
planning as lower priority than PTV1, although usually at a higher priority than normal 
structures other than spinal cord and brainstem. 


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9.4.2 
Definition of Target Volumes for Post-Operative Patients 
CTV60: This volume will receive 2 Gy per day. CTV60 will include the primary tumor bed (based 
on preoperative imaging, preoperative physical exam/endoscopy, operative findings, pathologic 
findings) plus regions of grossly involved lymphadenopathy. CTV60 may include the broader 
operative resection bed in the region of gross primary and nodal disease. The entire nodal 
regions in the involved hemi-neck may be included in CTV60 at the discretion of the investigator 
for perceived higher-risk cancers. 
CTV60 will also include the ipsilateral pathologically positive hemineck (if both sides of the neck 
are proven pathologically positive, CTV60 will include both sides). This generally means 
encompassing nodal levels 2a, 3, and 4 for most cases. Nodal levels 1, 2b, 5a, and 5b are 
included in CTV60 in selected circumstances. For example, level 1 should be included for oral 
cavity cancer but is not mandatory for larynx cancer. Level 5a should be included for oropharynx 
cancer but is not mandatory for larynx cancer. 
CTV56: This will include all other lesser risk regions in the operative bed (that were involved 
with surgery in any way) but felt to be at risk for harboring microscopic cancer that do not meet 
the criteria for CTV60. For example, this could apply to the broad operative bed, the 
contralateral hemineck being irradiated electively. This volume should not directly approach the 
skin < 5 mm. This volume will receive 1.85 Gy per day. 
CTV66 Optional: This volume may be defined at the discretion of the treating radiation 
oncologist. This would include regions felt to be at particularly high risk for recurrence (eg, an 
area of the extracapsular extension or positive margin of resection). Note: This area will be 
receiving a daily fraction size of 2.2 Gy and thus, the volume of CTV66 should be kept as small as 
possible. 
Planning Target Volumes (PTVs): In general, the PTV should not extend beyond the skin surface, 
except if the skin was involved with tumor. If it does extend beyond the skin surface, the 
application of bolus material over this portion of the PTV may be considered. It is also allowable 
to define 2 PTV’s for a given CTV: 1) PTV for planning, which extends beyond the skin surface 
and is used for planning treatment segments; and 2) PTV Evaluation (PTV_Eval), which does not 
reach the skin surface within 2 mm and is used for evaluation of the dose volume histogram to 
determine if treatment goals have been met. 
Dose to Supraclavicular Nodal Region 
Regardless of whether technique 1 (Match) or technique 2 (No Match) is used, the dose to the 
supraclavicular nodal region may be limited to 56 Gy for the non-operated, node negative 
hemineck, and for an involved hemi-neck if level 4 nodes were dissected and found to be 
negative. 
IMRT Dose Prescription to PTVs in the Resected Patient 
The prescribed radiotherapy dose will be 60-66 Gy in 2 Gy once-daily fraction size 5 days a week. 
For inverse planning IMRT, the goal is for 95% of the PTV60-66 Gy to receive ≥ 2 Gy with a 
minimum dose (cold spot) of no less than 56 Gy. It is recognized that portions of the PTV60-66 
Gy close to the skin may receive significantly less than 56 Gy. 


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9.4.3 
Definition of Normal Tissues/Organs at Risk (OAR) 
NOTE: Only the parts of the normal tissues/organs at risk outside the PTVs will be considered for 
dose optimization purposes. 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The inferior border of the spinal 
cord for this trial is at approximately T3-4 (i.e., just below the lowest slice level that has PTV on 
it). The spinal cord shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord = cord + 5 mm 
in each dimension. This is irrespective of whether or not IGRT is used. 
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where it 
meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall be 
defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume 
(PRV) brainstem shall be defined. The PRVbrainstem = brainstem + 3 mm in each dimension. 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to keep 
the lip dose much lower than the oral cavity dose. The definition of lips is self-explanatory. The 
oral cavity will be defined as a composite structure consisting of the anterior ½ to 2/3 of the oral 
tongue/floor of mouth, buccal mucosa, and palate. 
Parotid Glands: Parotid glands will be defined in their entirety (superficial and deep lobes) based 
on the treatment planning CT scan. Parotid gland volume may include portions of any of the 
CTVs if the primary or nodal volumes involved or closely approached the parotid, although they 
can overlap the PTVs.  
Submandibular Glands: Submandibular glands will be defined in their entirety based on the 
treatment planning CT scan. Submandibular gland volume may include portions of any of the 
CTVs if the primary or nodal volumes involved or closely approached the submandibular, 
although they can overlap the PTVs.  
Oropharynx: This will be defined as the “uninvolved” posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior pterygoid 
plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). 
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
oropharynx and extends to the thoracic inlet. 
Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular prism shaped” volume that 
begins just inferior to the hyoid bone and extends to the cricoid cartilage inferiorly and extends 
from the anterior commissure to include the arytenoids. This includes the infrahyoid but not 
suprahyoid epiglottis. 
Obviously, for patients who have had a total laryngectomy, this structure is not applicable. 
Mandible: This includes the entire boney structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs. 


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Unspecified Tissue Outside the Targets: This will be defined as tissue located between the skull 
base and thoracic inlet that is not included in either the target volumes or the normal tissues 
described above. 
In cases of weight loss > 10% or significant shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask will be adjusted or re-made in order to preserve 
adequate immobilization and that a repeated simulation CT be performed to assess the dose 
distributions in the current anatomy. Whether or not a new IMRT plan will be generated is at 
the discretion of the treating physician. If a new plan is made, the targets should be the same as 
those used for the initial plan. The new CT dataset should be used for IGRT image registration 
when the patient’s shape changes significantly. 
9.4.4 
IMRT Dose Constraints to Normal Structures 
Spinal Cord: The PRVcord (as defined in Section 9.4.3) should not exceed 48 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should not exceed 
50 Gy to any volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV should be 
given the highest priority. 
Brainstem: The PRVbrainstem (as defined in Section 9.4.3) should not exceed 52 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
PRVbrainstem should be given less priority than the PRVcord but more priority than the other 
critical structures listed below. Brainstem dose should be kept as low as possible in order to 
minimize nausea and vomiting especially since patients will be receiving cisplatin, which is highly 
emetogenic. 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. 
Oral Cavity: Reduce the dose as much as possible when not registered as the primary site of 
disease. The mean dose should be < 30 Gy for the non-involved oral cavity. Efforts should also 
be made to avoid hot spots (> 60 Gy) within the non-involved oral cavity. 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a median dose of < 20 
Gy and/or a mean dose of < 26 Gy. Taking into account new data suggesting monotonous 
improvement in saliva as dose is reduced, without a threshold the objective will be to reduce 
the mean doses to both parotid glands as much as possible. (Variation Acceptable: 26-30 Gy). 
For the parotid glands, the mean dose, median dose, and V25 Gy for each gland will be 
evaluated. 
Contralateral or ipsilateral submandibular gland: If contralateral level Ib is not a target, aim to 
reduce mean contralateral submandibular gland to < 26 Gy. Ipsilateral submandibular gland 
sparing may also be feasible in certain cases so similar dose constraints are recommended. 
(Variation Acceptable: 26-30 Gy). For the submandibular glands, the mean dose, median dose, 
and V25 Gy for each gland will be evaluated. 
Oropharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) 
treatment goals include: 1) No more than 33% of the oropharynx exceeds 50 Gy; 2) Mean dose < 
45 Gy; 3) No more than 15% of the Oropharynx exceeds 60 Gy. 


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Cervical Esophagus: Reduce the dose as much as possible. For oral or oropharyngeal cancer, 
some recommended (but not mandatory) treatment goals include: 1) No more than 33% of the 
esophagus exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of the esophagus 
exceeds 54 Gy. For larynx cancer, higher doses are expected and permitted. Some 
recommended doses (but not mandatory) treatment goals include: 1) No more than 33% of the 
esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the esophagus 
exceeds 60 Gy. 
Glottic and Supraglottic Larynx (GSL): Reduce the dose as much as possible. The glottic larynx 
mean dose is recommended to be <20 Gy. If whole-neck IMRT is used under- dosage of PTV2/
PTV3 adjacent to the glottic larynx will be limited to <10% receiving < 95% prescribed dose (this 
under-dosage is similar to that caused by the laryngeal block inserted in the split-field IMRT. 
Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 66 Gy, however it is 
realized that this may not be possible for certain tonsil cancers and/or if there are large nodes 
abutting the mandible. 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside the 
targets can receive 74 Gy or more for patients with unresected disease. In the resected patient, 
for the typical case in which there is no CTV66, no more than 0.03cc or approximately 3x3x3 mm 
unspecified tissue can receive 66 Gy or more. When a boost is used to increase the dose to high 
risk regions to as much as 66 Gy, these numbers can be increased. In this case, no more than 
0.03cc or approximately 3x3x3 mm of the unspecified dose should exceed the boost dose value 
plus 10% or 72.6 Gy. 
9.5 
Critical Structures  
The following table outlines the various normal and critical structures. Institutional standards 
may be used instead. 
Standard Name 
Description 
GTV 
Primary tumor and involved nodes 
CTV_7000 
Primary tumor and involved nodes 
PTV_7000 
CTV to PTV expansion should be 5 mm minimal margin without 
IGRT; 3 mm minimal margin with Daily IGRT 
CTV_5600 
First Echelon nodal regions 
PTV_5600 
CTV to PTV expansion should be 5 mm minimal margin without 
IGRT; 3 mm minimal margin with Daily IGRT  
CTV_5000 
Lower risk nodal regions 
PTV_5000 
CTV to PTV expansion should be 5 mm minimal margin without 
IGRT; 3 mm minimal margin with Daily IGRT  
CTV_5250 
Lower risk nodal regions 
PTV_5250 
CTV to PTV expansion should be 5 mm minimal margin without 
IGRT; 3 mm minimal margin with Daily IGRT  
SpinalCord 
Spinal Cord 
SpinalCord_05 
Planning Risk Volume of 5 mm 


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Standard Name 
Description 
BrainStem 
Brainstem 
BrainStem_03 
Planning Risk Volume of 3 mm 
Parotid_L 
Left Parotid 
Parotid_R 
Right Parotid 
OralCavity 
Oral Cavity 
Lips 
Lips 
Mandible 
Mandible 
Pharynx 
Uninvolved posterior pharyngeal wall plus adjacent constrictor 
muscles; should not include PTVs 
Esophagus 
Cervical Esophagus 
Larynx 
Glottic/Supraglottic Larynx 
External 
External border of patient used to define Unspecified Tissue 
PTV_7000_8mm 
Minimum dose (cold spot within PTV1 not including portion of 
PTV near (<8mm) skin) defined for a point that is 0.03cc in size 
NonPTV_7000 
Maximum dose (hot spot > 1cc outside the PTVs) 
9.6 
Documentation Requirements for IMRT Approach 
• 
Pre-treatment Radiation therapy planning CT scan; 
• 
If IGRT is not used, then orthogonal images that localize the isocenter placement of 
IMRT are required.  
• 
Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Treatment breaks, if necessary, ideally should not exceed 5 treatment 
days at a time and 10 treatment days total. Treatment breaks should be allowed only for 
resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical 
reasons. Any treatment break(s) exceeding 5 treatment days for reasons other than toxicity/
illness will be considered a protocol deviation. 
All treatment plans are to be normalized to provide exactly 95% volume coverage of the PTV1 
with 70 Gy for patients with unresected disease. 
 
Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Total RT dose to PTV1 (to 95% of 
the PTV) 
70 Gy 
None 
None 
Minimum dose (“cold spot” 
within PTV1, not including 
portion of PTV near (<8 mm) 
skin) defined for a point that is 
0.03 cc in size 
66.5 Gy (equals 95% of 
prescribed dose) 
< 66.5 but > 63 Gy 
≤ 63 Gy 
Maximum dose (“hot spot” > 
1cc) within PTV1 
≤ 77 Gy 
> 77 but ≤ 82 Gy 
> 82 Gy 
Maximum dose (“hot spot” > 
1cc outside the PTVs) 
< 74 Gy 
74-77 Gy 
> 77 Gy 


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Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Total dose to PTV2 (to 95% of 
the PTV) 
56 Gy 
≥ 45 but < 56 Gy 
< 45 Gy 
Total dose to PTV3 (to 95% of 
the PTV) 
50-52.5 Gy 
≥ 40 but < 50 Gy 
< 40 Gy 
Total RT dose to spinal cord PRV 
(0.03 cc) 
≤ 50 Gy 
≥ 50 but ≤ 52 Gy 
> 52 Gy 
Definition of Spinal cord PRV 
Based on case review by Primary Investigator 
Overall RT treatment time 
< 47 days 
48-51 days (without a 
medically 
appropriate 
indication for delay) 
> 52 days 
(without a 
medically 
appropriate 
indication for 
delay). 
Non-Medically Indicated 
Treatment Interruptions 
0-2 
2-4 
> 4 
9.7 
RT Quality Assurance Reviews 
RT Quality Assurance Reviews will be done with participating radiation oncology investigators 
with regularly scheduled discussions. 
9.7.1 
Radiation Therapy / Adverse Events 
Grade 3-4 (CTCAE, v. 4.03) therapy-induced mucositis and/or dysphagia, which are enhanced by 
cisplatin, are expected to develop in about two thirds of patients. Nutritional evaluation prior to 
the initiation of therapy for a prophylactic gastrostomy (PEG) tube placement is highly 
recommended. Placement of a feeding tube should be recorded, as should use of a feeding tube 
during and after treatment (e.g., greater than or less than 50% of nutrition by tube). Other 
common radiation adverse events include: fatigue, weight loss, regional alopecia, xerostomia, 
hoarseness, transient ear discomfort, dysgeusia, headaches, loss of appetite, and skin erythema 
and desquamation within the treatment fields. 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much 
less common radiation adverse events include: tissue necrosis, secondary cancer, mandibular 
osteoradionecrosis (< 5% incidence with attention to the standard dental recommendations), 
and cervical myelopathy (< 1% with restriction of spinal cord dose to ≤ 45 Gy). 


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Summary of possible side effects of radiation therapy to the head and neck:  
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, more than 20 and up to 100 may have: 
• Sores in the mouth and/or throat which can be painful and make it very difficult to 
chew and or swallow foods 
• Mouth dryness or changes in taste and/or smell that may be permanent 
• Thick saliva 
• Hoarseness 
• Tanning or redness and/or irritation of the skin in the head and neck area being 
treated with radiation 
• Ear pain and/or pressure 
• Fatigue 
• Weight loss 
• Permanent hair loss in the area treated with radiation (face, chin, neck) 
• Loss of teeth or cavities in the teeth if strict dental care is not followed and/or 
hypersensitivity of teeth 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, from 4 to 20 may have: 
• Decrease in function of the thyroid gland that may require you to take thyroid 
replacement medicine to prevent you from feeling tired or sleepy 
• Serious damage to the jawbone, voice box, skin, or other parts of the head and neck 
that may require a major operation to correct and, rarely, can even be life 
threatening 
• Temporary pain or scarring around nerves in the shoulder that could cause 
numbness and/or weakness 
• Breathing problems 
• Difficulty with swallowing and eating for which you might need a long term or 
permanent feeding tube; possibility of inhaling food and/or liquids into the lungs – 
which could also result in pneumonia. This side effect is more likely for patients 
receiving radiation and cisplatin (Group 1). 
• Serious ear infections and/or hearing loss 
• Loss of hearing 
 


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10 
Study Drug (Cisplatin) 
Refer to the package insert for detailed pharmacologic and safety information 
10.1 
Description 
Cisplatin is a standard of care chemotherapeutic agent used to treat a myriad of malignancies, 
including HNSCC and salivary gland cancers. It works by binding DNA and causing crosslinks and 
adducts [52].  
10.2 
Formulation 
Each vial contains 10 mg of cisplatin (DDP), 19 mg of sodium chloride, 100 mg of mannitol, and 
hydrochloric acid for pH adjustment. One vial is reconstituted with 10 mL of sterile water. The 
pH range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous 
solution, each mL containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH.  
10.3 
Storage and Stability 
Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be 
protected from light if not used within 6 hours. The vials and injection should not be 
refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black 
precipitate within 30 minutes.  
10.4 
Administration 
Cisplatin is an IV chemotherapeutic agent approved to treat head and neck cancers. Cisplatin 
will be administered per institution’s standard of care practice. Common standard of care 
practice includes dosing cisplatin at 100mg/m2 IV q21 days starting on Day 1 of RT for 2-3 doses 
or dosing cisplatin at 30-40 mg/m2 IV on Monday or Tuesday of each week of RT for 6-7 total 
doses. Cisplatin will be infused per institutional guidelines. Patients who start on q21 day dosing 
may switch to weekly dosing if deemed necessary by the treating investigator. Per institutional 
guidelines, patients should receive vigorous hydration and electrolyte replacement. The use of 
prophylactic anti-emetics including a 5-HT3 inhibitor and dexamethasone should be used per 
ASCO Guidelines. A NK1 inhibitor such as aprepitant may be used per institutional guidelines. 
10.5 
Dose Modifications 
Dose modifications of cisplatin will be performed by the treating physician per each institution’s 
standard practice. The following are guidelines to aid in decision-making. Escalation of the 
cisplatin is not allowed once the dose level has been reduced. 
10.5.1 Suggested dose modifications 
Starting dose 
Dose level -1 
Dose level -2 
40 mg/m2 (weekly) 
30 mg/m2 (weekly) 
20 mg/m2 (weekly) 
 
Starting dose 
Dose level -1 
Dose level -2 
30 mg/m2 (weekly) 
20 mg/m2 (weekly) 
Discontinue cisplatin 
 
Starting dose 
Dose level -1 
Dose level -2 
100 mg/m2 (q21 days) 
75 mg/m2 (q21 days) 
50 mg/m2 (q21 days) 
 


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10.5.2 Hematologic Toxicity 
NCI CTCAE Toxicity Grade (v 4.03) 
Cisplatin dose at start of subsequent week 
Neutropenia 
1 (1500-1999/mm3) 
Maintain dose level 
2 (1000-1499/mm3) 
Maintain dose level 
3 (500-999/mm3) 
Hold dose for one week; if continues >7 days 
then decrease 1 dose level and resume when 
reaches grade 2.  
4 (<500/mm3) 
Hold dose for one week; if continues >7 days 
then decrease 1 dose level and resume when 
reaches grade 2. 
Neutropenic Fever (grade3 or 4) 
Hold dose at least one week; if ANC ≥1500 
then decrease 1 dose level. 
Thrombocytopenia 
1 (75,000/mm3 -LLN) 
Maintain dose level 
2 (50,000-74,999/mm3) 
Hold dose for one week; if continues >7 days 
then decrease 1 dose level and resume when 
reaches grade 1 
3 (25,000-49,999/mm3) 
Hold dose for one week; if continues >7 days 
then decrease 1 dose level and resume when 
reaches grade 1 
4 (<25,000/mm3) 
Hold dose for one week; if continues >7 days 
then decrease 1 dose level and resume when 
reaches grade 1 
10.5.3 Non-hematologic Toxicity  
NCI CTCAE Toxicity Grade (v 4.03) 
Cisplatin dose at start of subsequent 
week 
Renal-serum creatinine 
Cr ULN-1.5mg/dL or CrCl >50 mL/min 
Maintain dose level 
>1.5mg/dL and CrCl 40-50 mL/min 
Decrease by 1 dose level 
Cr >1.5mg/dL and CrCl <40 
Hold drug until CrCl is >50mL/min the 
resume after decrease by 1 dose level 
Fatigue 
Grade 3 
Decrease by 1 dose level 
Nausea/vomiting 
≤ Grade 2 with maximal medical 
management 
Maintain dose level 
Intolerable grade 2 with maximal 
medical management 
Decrease by 1 dose level  
≥ Grade 3 with maximal medical 
management 
Hold drug until ≤ grade 2 then resume 
at one lower dose level 
Mucositis in RT field 
Hold drug until ≤ grade 3 


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Grade 4 
 Hearing impairment or tinnitus 
 
≤ Grade 1 
Maintain current dose 
Grade 2 
Decrease dose by one dose level 
Grade 3 
Hold drug until ≤ grade 1 then resume 
at one lower dose level 
Grade 4 (hearing impairment) 
Discontinue cisplatin 
Other grade 4 non-hematologic AEs 
Hold drug until ≤ grade 1 then resume 
at one lower dose level 
10.6 
Adverse Events 
• 
Nephrotoxicity (kidney damage) is a major concern. The dose is reduced when there 
is a significant change in the patient's creatinine clearance (a measure of renal 
function). Adequate hydration and diuresis is used to prevent renal damage. The 
nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen 
species and in animal models can be ameliorated by free radical scavenging agents 
(e.g., amifostine). Nephrotoxicity is a dose-limiting side effect [53]. 
• 
Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction 
studies before and after treatment. Common neurological side effects of cisplatin 
include visual perception and hearing disorder, which can occur soon after 
treatment begins [54]. While triggering apoptosis through interfering with DNA 
replication remains the primary mechanism of cisplatin, this has not been found to 
contribute to neurological side effects. Recent studies have shown that cisplatin 
noncompetitively inhibits an archetypal, membrane-bound mechanosensitive 
sodium-hydrogen ion transporter known as NHE-1 [55]. It is primarily found on cells 
of the peripheral nervous system, which are aggregated in large numbers near the 
ocular and aural stimuli-receiving centers. This noncompetitive interaction has been 
linked to hydroelectrolytic imbalances and cytoskeleton alterations, both of which 
have been confirmed in vitro and in vivo. However, NHE-1 inhibition has been found 
to be both dose-dependent (half-inhibition = 30 µg/mL) and reversible [56]. 
• 
Nausea and vomiting: Cisplatin is a highly emetogenic chemotherapy, but this 
symptom is managed with prophylactic antiemetics (ondansetron, granisetron, etc.) 
in combination with corticosteroids. Aprepitant combined with ondansetron and 
dexamethasone has been shown to be better for highly emetogenic chemotherapy 
than just ondansetron and dexamethasone. 
• 
Ototoxicity (hearing loss): There is at present no effective treatment to prevent this 
side effect, which may be severe although doses >50 mg/m2 may be associated with 
a higher risk of hearing loss. Audiometric analysis may be necessary to assess the 
severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may 
also cause ototoxicity, and the administration of this class of antibiotics in patients 
receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides 
and cisplatin may be related to their ability to bind to melanin in the stria vascularis 
of the inner ear or the generation of reactive oxygen species. 
• 
Electrolyte Disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia, and 
hypocalcaemia. The hypocalcaemia seems to occur in those with low serum 
magnesium secondary to cisplatin, so it is not primarily due to the cisplatin. 


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• 
Myelotoxicity: This agent can also cause profound bone marrow suppression [57]. 
• 
Hemolytic anemia can be developed after several courses of cisplatin. It is suggested 
that an antibody reacting with a cisplatin-red-cell membrane is responsible for 
hemolysis [58]. 
• 
Other potential adverse events include: ocular disturbances, renal toxicity (with an 
elevation of BUN and creatinine and impairment of endogenous creatinine 
clearance, as well as renal tubular damage, which appears to be transient), and 
hyperuricemia. Much more severe and prolonged toxicity has been observed in 
patients with abnormal or obstructed urinary excretory tracts. 
Summary of possible side effects related to cisplatin are: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Anemia, which may cause tiredness or may require blood transfusions 
• Bruising, bleeding 
• Kidney damage, which may cause swelling, may require dialysis 
• Hearing decrease, including ringing in ears 
• Change in taste 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cisplatin, from 4 to 20 may have: 
• Allergic reaction, which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Confusion 
• Difficulty with balance 
• Numbness in the fingers and toes 
• Low blood pressure 
• Low magnesium in the blood, which may cause heart beat irregularities that are possible 
life threatening 
 
RARE, AND SERIOUS 
In 100 people receiving cisplatin, 3 or fewer may have: 
• Cancer of bone marrow later in life caused by chemotherapy  
• Seizure 
10.6.1 Risks of Phlebotomy 
Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or 
swelling in the area of the insertion, bleeding at the site of the needle puncture, light 
headedness, fainting, and very rarely, local infection, which may be severe. These risks are 
reduced by the fact that the blood will be drawn by a qualified physician, nurse or phlebotomist 
(a professional trained to draw blood). 
10.7 
Supply 
Cisplatin is manufactured by multiple sources and commercial drug will be used in this study. 


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11 
STUDY DRUG (BMX-001) 
11.1 
Names, Classification, and Mechanism of Action 
BMX-001 (Figure 2) also known as MnTnBuOE-2-PyP5+ (manganese butoxyethyl pyridyl 
porphyrin), is a metalloporphyrin antioxidant that has anti-inflammatory, anti-oxidant, and anti-
tumor functions. A series of metalloporphyrins have undergone preclinical evaluation, and BMX-
001 represents one with increased catalytic potency along with high lipophilicity. This class of 
metalloporphyrins leads to inactivation of reactive oxygen species and in turn leads to reduction 
of oxidative stress. The lipophilicity of BMX-001 leads to its accumulation in the brain 
parenchyma, and it has been shown to cross the blood-brain barrier. Because the vasculature of 
most mammalian species is highly sensitive to an oxidative shift, there is a concern for blood 
pressure monitoring in studies of the metalloporphyrin compounds. Studies in Sprague-Dawley 
rats showed that intravenous delivery of metalloporphyrin could lead to transient hypotension 
[59]. In this same study, mice, guinea pigs, dogs, and baboons received intravenous delivery of 
metalloporphyrins with less effect on blood pressure. BMX-001 was patented by Duke 
University and has been licensed to BioMimetix JV, LLC. 
 
Figure 2:  Chemical Structure of BMX-001 
11.2 
Potential Benefits 
The potential benefits may include protection against mucositis and xerostomia caused by RT of 
the subject’s head and neck cancers [19]. Because this clinical protocol is experimental, it cannot 
be guaranteed that subjects will receive any benefit as a result of participating in this research 
study. The information collected in this research may help scientists better understand the 
mechanisms involved in oxidative stress as it pertains to treatment of head and neck cancer. If 
such an understanding emerges from this research, it may benefit society by furthering the 
development of improved treatment methods for newly diagnosed head and neck cancers in the 
future.  
11.3 
Packaging and Labeling 
11.3.1 Drug Product Formulation and Manufacture 
The drug will be supplied by BioMimetix JV, LLC. The drug substance (1.2 kg of solid) was 
manufactured and stored according to cGMP by Albany Molecular Research, Inc. (AMRI). 


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BioMimetix JV, LLC, has contracted with AMRI (Glasgow) Ltd. to manufacture single dose vials of 
sterile BMX-001 for injection. Manufacturing will be conducted on AMRI's Flexicon FPC50W 
filling machine, which is dedicated for aseptic GMP manufacturing within a clean room suite. 
Manufacturing will include batch pre-filtration and aseptic filtration and filling in accordance 
with AMRI Glasgow's validated process.  
BMX-001 will be formulated as a solution in 0.9% saline at 10 mg/mL, aseptically filtered and 
filled to 2 mL in a 5 mL Type 1 clear glass vial, sealed with a 20 mm Flurotec serum stopper and 
flip off aluminum overseal. A nitrogen overlay will be applied to each vial following filling and 
prior to stoppering. 
In-process testing will include pre-filtration bioburden, post-use filter integrity test, and in-
process weight checking. Release tests and specifications for BMX-001 for injection are currently 
under development, but will be established before manufacturing of the clinical batch 
commences. These will include sterility (USP <71>), bacterial endotoxins (USP <85>), particulate 
matter (USP <788>), appearance, color and clarity, pH, osmolality, assay, and purity. 
The clinical batch of drug product will be placed on stability and tested for the duration of its use 
during the clinical trials. 
11.3.2 Labels for BMX-001 for Injection, 10 mg/mL 
An exemplary label for the BMX-001 for Injection, 10 mg/mL is reproduced in Figure 3.  
BMX-001 for Injection, 10 mg/mL 
Lot # P07715 
Administer SQ, ≤1.4 mL/site. 
Caution:  New Drug – Limited by Federal 
Law to Investigational Use 
Emergency contact:  Dr. Shayne Gad, 
cell 919-618-0523 
 
Store at RT 
Figure 3:  Exemplary Label for BMX-001 for Injection, 10 mg/mL 
11.3.3 Syringe and Label for Administration of BMX-001 for Injection, 10 mg/mL 
A pharmacist at the clinical study center will prepare the loaded syringe(s) and needle(s) that 
will be used for subcutaneous administration of the appropriate dose of BMX-001 for Injection, 
10 mg/mL (from the Dosing Levels Table in Section 11.5 and 11.6) to the clinical subject. The 
clinical study center pharmacist will adhere to all USP 797 standards for preparation of sterile 
products. The subcutaneous needle will be capped and the syringe will be stored at room 
temperature until use, which should occur within 2 hours.  
11.3.4 Multi-Dose Kits 
The vials, labeled as described in Section 11.3.1, are packaged in paperboard cartons. The carton 
label includes the information indicated in Figure 4, where "XXX" is replaced by the number of 
vials contained in the carton. 


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Lot # P07715 
 
 
 
 
 
 
 
Store at RT 
 
BMX-001 for Injection, 10 mg/mL Multi-Dose Kit 
 
Contents:  XXX Single-Dose Units @ 20 mg each 
 
Caution:  New Drug - Limited by Federal Law to 
Investigational Use. 
 
Emergency contact: Dr. Shayne Gad, cell 919-618-0523 
Figure 4:  Exemplary Label for Multi-Dose Kits 
11.4 
Supply, Receipt, and Storage 
The multi-dose kits described in Section 11.3.4 will be shipped by overnight delivery to the local 
clinical center. These kits will be stored at room temperature, in a locked, physically secure 
environment, separate from other drug products, according to the local clinical center 
pharmacy's standard procedures for storage of investigational drug products. Drug 
accountability records will be maintained by the local clinical center for all clinical trial supplies. 
The stability of the drug product during the course of the clinical trial will be established by long-
term stability studies currently underway at AMRI (Glasgow) Ltd. At the present time, no 
significant drug degradation has been observed under storage conditions. 
11.4.1 Compliance and Accountability 
Drug accountability records will be maintained for all clinical trial supplies. 
11.4.2 Disposal and Destruction 
All empty and partially used clinical trial supplies will be destroyed in accordance with the 
institution’s requirements for an investigational agent. Disposition of all unused boxes of study 
drug will be carried out according to instructions provided by BioMimetix JV, LLC, at the end of 
the study after drug accountability is performed. The pharmacy will maintain detailed 
documentation of the number and identification of BMX-001 vials that are destroyed, and 
copies of these documents will be provided to BioMimetix JV, LLC. 
11.4.3 Dispensing and Preparation 
A pharmacist at the local investigative site will prepare the loaded syringe and needle that will 
be used for subcutaneous administration of the appropriate dose of BMX-001, Injection Solution 
10 mg/mL, as indicated on the vial label, to the clinical subject. The BMX-001, Injection Solution 
10 mg/mL will be drawn from the vial described in Section 11.3.1. The subcutaneous needle will 
be capped and the syringe will be stored at room temperature until use, which should occur 
within 2 hours.  
11.5 
Phase 1 Administration by Dose Escalation at levels below established MTD  
The RP2D of BMX-001 has been established in a concluded Phase 1 trial with high-grade glioma 
patients. This head and neck cancer Phase 1 trial evaluated the two lower doses of BMX-001 and 
found no dose-limiting toxicities of BMX-001 in combination with cisplatin and also with 
radiation of the head and neck.  


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BMX-001 was administered subcutaneously as a loading dose before starting concurrent 
chemoradiation (days -4 through 0 depending on patient scheduling). After the loading dose, 
the maintenance dose levels were given two times per week for 8 weeks. The starting dose level 
was 7 mg loading dose. The BMX-001 dose was then escalated to 14 mg loading dose. After the 
loading dose, the BMX-001 maintenance dose was administered 7 mg twice a week.  
The corresponding volumes of BMX-001, Injection Solution 10 mg/mL associated with the 
loading doses are as follows: 
0.7 mL/subject loading dose = 7 mg/subject  
1.4 mL/subject loading dose = 14 mg/subject  
 
The corresponding maintenance doses would be equivalent to the following:  
0.35 mL/subject maintenance dose = 3.5 mg/subject  
0.7 mL/subject maintenance dose = 7 mg/subject  
 
BMX-001 is administered by subcutaneous injection of a sterile 10 mg/mL solution in saline. The 
subcutaneous injections are at any optimum site on the torso, the upper leg or upper arm. 
Maintenance doses are approximately one-half the size of the loading dose and should be 
administered twice weekly. The first maintenance dose should be delivered either 3 or 4 days 
after the loading dose and subsequent maintenance doses delivered at 3 to 4 day intervals to 
average 2 doses per week. 
Table – Dosing Levels for Groups I & II 
 
Group I 
Group II 
Loading Dose 
7 mg/Subject 
14 mg/Subject 
Maintenance Dose 
 
 
1 
3.5 mg 
7 mg 
2 
3.5 mg 
7 mg 
3 
3.5 mg 
7 mg 
4 
3.5 mg 
7 mg 
5 
3.5 mg 
7 mg 
6 
3.5 mg 
7 mg 
7 
3.5 mg 
7 mg 
8 
3.5 mg 
7 mg 
11.6 
Phase 2 Expanded 
Because this Phase 2 trial involves neck radiation instead of brain and cisplatin instead of TMZ, a 
safety lead in studying the RP2D of 28 mg/subject load and 14 mg/subject maintenance dose 
will be part of Phase 2 expansion. 
 
No more than 1.4 mL is to be administered at a single injection site. Thus a 28 mg dose will be 
administered in two equal portions (14 mg), taken from different vials and injected via separate 
syringes and needles at two different sites.  
 
 


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Dose Level for Phase 2 
Loading Dose 
28 mg/Subject 
Maintenance Dose 
 
1 
14 mg 
2 
14 mg 
3 
14 mg 
4 
14 mg 
5 
14 mg 
6 
14 mg 
7 
14 mg 
8 
14 mg 
 
11.7 
Compliance and Accountability 
Drug accountability records will be maintained for all clinical trial supplies. Study team staff will 
schedule all of the patient’s appointments and a calendar may be provided to the patient.  
Regardless of the reason for holding study drug treatment, the maximum allowable length of 
treatment interruption is 3 weeks. 
11.8 
Concomitant Medications 
Because corticosteroids are anti-inflammatory and could interrupt oxidative stress, patients will 
be required to be on stable or decreasing corticosteroids dose at the time of the study enroll-
ment. If patient is required to have additional steroids such as an allergic reaction, adrenal 
insufficiency, increased neurological symptoms, and/or increased intracranial pressure, then 
corticosteroids can be added at the discretion of the treating physician and minimal dose, if 
deemed medically appropriate, will be utilized to control symptoms. 
11.9 
Dose Modifications 
If adverse events occur that require holding BMX-001, the dose will remain the same once 
treatment resumes. 
NCI CTCAE toxicity 
BMX-001 dose 
Hypotension 
 
≤ Grade 2 
Maintain current dose. For grade 2 
may give IV fluids and place patient 
in Trandeleburg position. 
≥ Grade 3 
Discontinue BMX-001. Supportive 
care as below. 
Injection site reaction 
 
≤ Grade 2 
Administer acetaminophen 325-650 
mg PO 30 minutes prior to injection. 
Intolerable grade 2  
Hold drug until ≤ grade 1 then 
resume. Supportive care as below. 
≥ Grade 3  
Discontinue BMX-001. 


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NCI CTCAE toxicity 
BMX-001 dose 
Other ≥ grade 3 attributable to 
BMX-001 
Discontinue BMX-001. 
Electrocardiogram QT corrected 
 interval prolonged 
 
Grade 1 (Average QTc 450 - 480 ms) Maintain current dose.   
Grade 2 (Average QTc 481 - 500 ms) Hold BMX-001 pending review by 
sponsor.  Refer to cardiology.    
 
ECG should be re-checked in 
approximately 1 week after the QTc 
prolongation was first observed or 
more frequently as clinically 
indicated.   
Grade 3 (Average QTc >= 501 ms; 
>60 ms change from baseline) 
Discontinue BMX-001.  
Regardless of the reason for holding study drug treatment, the maximum allowable length of 
treatment interruption is 3 weeks. 
11.10 Management Guidelines for Potential BMX-001-induced Toxicities  
Any toxicity associated or possibly associated with BMX-001 treatment should be managed 
according to standard medical practice unless as specified above. The primary anticipated 
toxicity is hypotension, which should resolve within 30-60 minutes.  
11.10.1 Post Drug Administration Monitoring 
Subjects should be observed for a minimum of 2 hours after administration of the initial loading 
dose of BMX-001 and for a minimum of 1 hour after subsequent doses. Monitoring should 
include evaluation of blood pressure, heart rate, and skin reaction. Blood pressure and heart 
rate will be measured pre-dose and then after 30 (±5), 60 (±5), and 120 (±10) minutes on the 
loading dose. It will be checked pre-dose, 30 (±5), and 60 (±5) minutes all other days of BMX-001 
administration. The skin reaction at the injection site should be evaluated at the same time 
blood pressure and heart rate are monitored. Site(s) of prior drug injection will be inspected 
before each new drug administration.  
After discharge, patient should be advised to be alert for potential symptoms of low blood 
pressure (i.e., dizziness, fainting, lightheadedness, blurry vision, weakness, nausea, vomiting, 
including exaggeration of one of the previous symptoms when transitioning from lying or sitting 
to standing). If these symptoms occur after discharge, the patient should lie down, elevate 
his/her feet and contact their health care provider if the symptoms persist. 
11.10.2 Hypotension 
If after drug therapy, the blood pressure drops > 20 mm Hg (systolic) from the pre-injection 
blood pressure level, place the patient in supine position and treat as follows:  
Mild hypotension (systolic > 90 mm Hg and < 110 mm Hg, or postural hypotension only) observe 
patient with repeated measures of blood pressure and heart rate every 10 minutes and expect 


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resolution within 30-60 minutes. Observe patient in the outpatient setting until blood pressure 
returns to normal and patient has no hypotensive or postural hypotensive symptoms. 
Moderate hypotension (systolic > 70 mm Hg and < 90 mm Hg) treat with i.v. fluids (normal saline 
or Ringer’s lactate) with repeated measures of blood pressure and heart rate every 10 minutes 
until systolic BP > 110 mm Hg. Observe patient in the outpatient setting until blood pressure 
returns to normal and patient has had no hypotensive or postural hypotensive symptoms for at 
least 1 hour. 
Severe hypotension (systolic < 70 mm Hg) treat with bolus i.v. fluids (normal saline or Ringer’s 
lactate) with repeated measures of blood pressure and heart rate every 5 minutes until systolic 
BP > 110 mm Hg. If resolution is not prompt, consider evaluation for underlying cardiovascular 
disease (including ECG) and urgent consultation with critical care team. Observe patient until 
blood pressure returns to normal and patient has had no hypotensive or postural hypotensive 
symptoms for at least 1 hour. 
11.10.3 Local Skin Reaction 
Skin discoloration is expected due to the color of the drug product and is not an adverse 
reaction. For reactions such as local pain, itching or erythema, initial treatment may include cold 
pack, ibuprofen for pain and observation every 30 minutes times 2 and then hourly until ≤ grade 
1 and patient is comfortable. 
For significant edema or lipodystrophy, treat with cold pack, elevation of injection site and 
observation every 30 minutes times 2 and then hourly until ≤ grade 1 or patient is comfortable 
and stable. 
For severe reactions (≥ grade 3: ulceration or necrosis; severe tissue damage) operative 
intervention may be indicated, seek surgical consult. 
11.10.4 Prolongation of QTc Interval and Management 
As of April 2019 there have been reports of three subjects with a QT prolongation present after 
a BMX-001 loading dose (28 mg/subject) that was not present at baseline.  Prolongation of QTc 
interval has not been observed in preclinical studies of BMX-001.   
 
In the BMX-HN-001 study, the prolonged QT interval presented in a subject at the 30 minute 
and 60 minute post-dose ECG. 
 
In the BioMimetix Multiple Brain Metastases study, the prolonged QT interval presented in a 
subject at the 30 minute and 60 minute post-dose ECG. 
 
In the BioMimetix Multiple Brain Metastases, the prolonged QT interval presented in a subject 
at the 60 minute post-dose ECG. 
 
In all cases Electrocardiogram QT corrected interval prolonged did not exceed a grade 2 
(average QTc 481 - 500 ms) according to CTCAE. 
 
No action with regards to BMX-001 was taken due to these events and the subjects are 
continuing on the study and the QT prolongation appears to have resolved.     


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At the time of this protocol amendment, 40 subjects have received a loading dose of BMX-001 
across 4 different trials.  The percentage of subjects presenting with QTc prolongation after the 
loading dose equates to 7.5%.  BioMimetix has reviewed all of the data for the subjects and 
there were no QTc prolongation outside of the three mentioned above.     
 
If a subject develops prolonged QT after receiving a dose of BMX-001, the subject should be 
referred to cardiology for work up and the case should be reviewed with the BioMimetix 
Medical Monitor to determine further dosing of BMX-001 and inclusion in the study.  
Additionally, levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range.  Finally, concomitant 
therapies should be reviewed and adjusted as appropriate for medications with known QT-
prolonging effects. 
 
If the cause is not identified and the investigator believes it is appropriate, particularly if QTc 
remains elevated, study drug may be interrupted, and an ECG should be re-checked in 
approximately 1 week after the QTc prolongation was first observed or more frequently as 
clinically indicated. If QTc has recovered or improved and the investigator believes it is safe to 
do so, continuing BMX-001 therapy should be considered if previously held. 
 
In any case, if a Grade 3 QTc interval (CTCAE) is identified, BMX-001 should be discontinued for 
that patient.   
 
11.11 Dose-Limiting Toxicity (DLT) 
Toxicities will be graded according to the NCI CTCAE version 4.03 criteria. DLTs will be defined as 
any of the following events that are at least (possibly, probably, or definitely) attributable to 
BMX-001 during the study. The DLT period includes from the start of BMX-001 through 4 weeks 
after CRT concludes. 
A dose limiting toxicity is defined as an adverse event or laboratory abnormality that is: 
a) assessed as unrelated to disease progression, intercurrent illness, or concomitant medica-
tions; b) occurs during and/or following the first dose of BMX-001; and c) meets any of the 
following criteria: 
11.11.1 Non-hematologic 
The occurrence of non-hematologic grade 3 or greater adverse events considered to be possibly, 
probably, or definitely related to BMX-001 during treatment with BMX-001, excluding grade 3 
alopecia and elevation in alkaline phosphatase, grade 3 nausea or vomiting unless occurring 
despite the use of standard anti-emetics. 
> 14 day delay to re-treat due to failure to resolve any grade 3 or greater non-hematologic drug-
related toxicity to re-treatment criteria or pre-treatment baseline. 
11.11.2 Hematologic 
Occurrence of any of the following hematologic adverse events will be defined as DLT: 
1) NCI CTCAE version 4.03 grade 3 febrile neutropenia or grade 4 neutropenia (ANC, 
including bands, ≤0.5 x 109 /l); 


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2) NCI CTCAE version 4.03 grade 3 thrombocytopenia (platelet count of ≤ 50x109/l); 
3) > 14 day delay to re-treat due to failure to resolve hematologic toxicity to re-treatment 
criteria. 
4) Grade ≥3 anemia 
11.11.3 Other Considerations 
Inability to complete 75% of the planned radiation dose. 
11.12 Adverse Events 
There is a completed Phase 1 trial and ongoing Phase 2 trial for patients with newly diagnosed 
high grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001 (BMX-
HGG study). In the Phase 1 trial, there was one dose-limiting toxicity of grade 3 tachycardia and 
grade 3 hypotension. The DLT in this subject occurred with the loading dose (42 mg sc). The 
patient was treated with fluids and hospital admitted for observation for 24 hours during which 
time the hypotension and tachycardia resolved. The cardiac rhythm was a sinus tachycardia and 
no other cardiac toxicity was observed. The tachycardia was assumed to have resulted from 
hypotension occurring following the sub-cutaneous injection of BMX-001 (42 mg). After the 
loading dose of BMX-001 and the described DLT, the subject continued on study and experienced 
no tachycardia or hypotension following administration of the subsequent 16 maintenance doses 
(20 mg sc).  
The most common related toxicity see in this Phase 1 trial was injection site reaction and all of 
these have been grade 1. There is no apparent toxicity to end organ tissues or bone marrow. 
This head and neck study is designed to determine the tolerability and safety of this agent with 
concurrent radiation therapy and cisplatin.  
Studies have been performed using intravenous infusions of a related metalloporphyrin in 
multiple models including rats, mice, dogs, guinea pigs, and baboons with the finding of dose-
related hypotension [59]. Metalloporphyrin compounds being evaluated are potent, catalytic 
antioxidants and have the potential to scavenge superoxide within the vascular system and 
thereby change the balance of superoxide and nitric oxide in the microvasculature. This would 
augment the vasodilating activity of nitric oxide and lead to hypotension [59]. This has been 
found in animal models to be a significant, but transient side effect and, therefore, blood 
pressure monitoring is essential in this proposed clinical trial of a metalloporphyrin compound. 
Studies of rats, mice, and monkeys have been performed with BMX-001 and have shown 
transient, dose-related hypotension. Hypotension is related to plasma Cmax levels and 
subcutaneous administration significantly reduces the risk of this toxicity in mice and primates 
(unpublished data per BioMimetix JV, LLC). We have designed this protocol to monitor blood 
pressure closely. Preliminary data suggests that the dose-limiting toxicity will be local irritation 
at the subcutaneous injection site. This dose-limiting toxicity is expected to be related to the 
concentration of the administered drug and the volume administered rather than to subject 
body size. 
Because of the development of transient hypotension in rat models, patients will undergo blood 
pressure monitoring before, during, and after the BMX-001 injections. In primate studies, the 
primary toxicity seen was skin reaction/irritation due to subcutaneous injection. Care will be 
taken to limit the volume of the injections to no more than 1.4 mL per site.  


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A summary of the possible adverse side effects that could be associated with BMX-001 
administration is below. These possible side effects are dose-dependent, and the relatively low 
doses of this drug planned in this study have not been associated with side effects in animals 
other than those related to the color of the injected drug. 
The most common side effects (expected to occur in more than 30% of subjects) are: 
• 
Red to brown discoloration of the skin at the injection site which may take up to several 
weeks to resolve 
• 
Irritation at the site of the injection of the drug under the skin 
• 
Transient tachycardia from the study drug  
 
Less common side effects (expected to occur in 10-30% of subjects) are: 
• 
Transient pain at the site of the injections of the drug under the skin 
• 
Local histamine release which could be caused by the study drug. This could cause 
pruritus (itching), erythema (redness), edema (swelling), urticaria (welts). This is 
expected to resolve within a couple of hours of injection 
Rare side effects (expected to occur in less than 10% of subjects) are: 
• 
Temporary hypotension (low blood pressure) 
• 
Malaise or “not feeling well” for a few hours 
• 
Prolongation of the QTc interval  
An additional possible side effect is: 
• 
Light-activated skin rash in response to sun exposure 
• 
Red to dark color of urine  
• 
It is also possible that previously unobserved and unexpected side effects could occur. 
 
11.13 Risk Classification 
The overall risk classification of this research is unknown. Clinical trials using BMX-001 in head 
and neck cancer patients have not been performed. 


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12 
Other Therapy 
12.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication. These may include analgesics, anti-
emetics, topical mouth rinses (Viscous lidocaine is allowed), skin creams/ointments, topical 
anesthetic/solution for laryngoscopy, etc. The use of amifostine as a radioprotector is not 
allowed. The use of granulocyte colony-stimulating factor or erythropoietin is not allowed. Any 
exceptions must be approved by a Principal Investigator or representative from BioMimetix JV, 
LLC. 
12.2 
Prohibited Therapies 
These are prohibited during the active study drug treatment period of the study and up until the 
first visit following completion of chemo therapy and radiation (~1 month). 
• 
Low-level laser treatment for OM 
• 
Amifostine (Ethyol®) 
• 
Benzydamine hydrochloride 
• 
Caphosol® or similar re-mineralizing solutions 
• 
Cevimeline hydrochloride (Evoxac®) 
• 
Glutamine applied topically 
• 
GM-CSF applied topically  
• 
IL-11 (Neumega®) 
• 
‘Magic mouthwashes’ or ‘Miracle mouthwashes’  
• 
Chlorhexidine 
• 
Hydrogen peroxide rinses 
• 
Tetracycline 
• 
Any other listed disallowed medications 
• 
MuGard™ 
• 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildanefil, tadalafil, 
or similar agents) or other drugs that in the judgment of the treating 
investigator could create a risk of a precipitous decrease in blood pressure are 
prohibited  
• 
Palifermin (Kepivance®) or other keratinocyte or fibroblast growth factor 
• 
Pilocarpine hydrochloride (Salagen®) 
• 
Povidone-iodine rinses 
• 
Steroid rinses 
• 
Episil® spray 
• 
Sucralfate in suspension form (use of sucralfate tablets is not proscribed) 
• 
Other biologic response modifiers – except systemic hematopoietic growth 
factors for the management of anemia or myelosuppression 
• 
Concurrent approved or investigational anti-cancer therapy (e.g., 
chemotherapy, immunotherapy, targeted therapy, hormone, and biologic 
therapy) other than the Protocol regimen 
• 
Other investigational agents 


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• 
Use of drugs known to lengthen QT intervals should be avoided or minimized. 
 


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13 
Screening and On-Study Tests and Procedures 
 
On-Study Tests and Procedures 
Evaluation 
Screeninga 
Base-
linea 
Wk  
1 
Wk  
2 
Wk  
3 
Wk  
4 
Wk  
5 
Wk  
6 
Wk  
7 
Wk  
8 
Wk 9 and 
Forwardb 
 
 
Day  
-4 to 
0 
 
 
 
  
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
History and 
physical examb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medicationsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
and heart ratec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differentialb 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMPb  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/aPTT 
X 
 
 
 
 
 
 
 
 
 
 
Serum beta-HCG 
 
Xj 
 
 
 
 
 
 
 
 
 
ECGd 
X 
X 
X 
 
 
X 
 
 
 
 
 
Mucositisb 
(clinical score) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Saliva productione 
(stimulated and 
unstimulated) 
 
X 
 
 
 
 
 
 
 
 
X 
XeQoLs, 
OMWQ-HN, 
DLQI 
Questionnaires 
 
X 
 
 
 
 
 
 
 
X 
X 
FACT-HN 
Questionnaire, 
PRO-CTCAE HN 
 
X 
 
 
 
 
 
 
 
X 
X 
Assessment of 
measurable 
disease by 
imagingf 
X 
 
 
 
 
 
 
 
 
 
X  
Toxicity 
Assessment 
X 
Ongoing 
X 
BMX-001g, h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cisplatin i 
 
 
X 
X 
X 
X 
X 
X 
Xi 
 
 
Radiation  
 
 
Daily Monday-Friday for 6-7 weeksk 
 
 
 
a Screening evaluation should be done within 21 days of starting BMX-001. The screening 
evaluation and baseline evaluation may be combined. Informed consent may be done within 
28 days of starting BMX-001.  
b Study assessments for History and Physical, medications, weight, vital signs, CBC w/ diff, 
CMP, and mucositis will be obtained at screening, baseline, weekly during therapy, and 
following therapy at clinic visits in which timing is scheduled under standard of care. 
Screening CBC with diff and CMP prior to the first dose of Cisplatin need not be repeated 
on week one for chemotherapy naïve subjects per institutional practice. Study visits 
following therapy (Week 9 and forward) will be under SOC and at minimum will include 
study data collection for the CRF at a post-therapy visit within 1 month of completion of 


Protocol #: BMX-HN-001 
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radiation (or within 1 month of completion of BMX-001 treatment) and at 6 and 12 months 
post radiation ± 1 month. Mucositis will be scored using the CTCAE version 4.03. Toxicity 
assessment will continue to be obtained during year 1 to identify late toxicities possibly 
related to SOC or with study drug. PT/aPTT will be measured once and can be done at 
either screening or baseline. 
c Blood pressure and heart rate will be measured pre-dose and then after 30 (±5), 60 (±5), 120 
(±10) minutes on the loading dose. It will be checked pre-dose, and post-dose at 30 (±5), 
and 60 (±5) minutes all other days of BMX-001 administration.  
d Phase 2:  ECG will be done at screening and will also be done pre-dose as well as at 60 (+ 
15) minutes after dosing on the loading day and on a maintenance dose injection day during 
week 1 and week 4, both pre and post dose at 60 (+ 15) minutes.   
e Saliva production will be measured on baseline and the post-therapy measurement will be 
obtained at clinic visit within 1 month of the end of radiation therapy and at 6 and 12 
months ± 1 month. If the post-therapy measurement cannot be obtained, this will not be 
considered a protocol deviation. 
f Assessment of measurable disease by imaging will be done according to SOC, i.e., during 
screening (up to 8 weeks prior to enrollment) and at approximately 3 and 12 months during 
follow-up. The 12-month (+/- 1-month post completion of radiation therapy or BMX-001 
treatment) follow-up imaging for this study will be a chest x-ray and is required as part of 
this study protocol and is specifically for research purposes.  
g For BMX-001, Day -4 to 0 will be the loading dose.  
h  For BMX-001, doses (50% of the loading dose) will be twice a week subcutaneously weeks 
1-8.  
i  Cisplatin 100mg/m2 IV q21 days starting Day 1 for 2-3 doses or 30-40mg/m2 IV per 
institutional standard each week of treatment x 6-7 total doses.  
j Female patients only: pregnancy test (serum beta-HCG) no more than 48 hours prior to first 
dose of BMX-001. 
k  Radiation therapy may extend into week 8. This is allowable and there is no limitation for 
radiation therapy extending into the 8th week of BMX-001 treatment. 
 
13.1 
Evaluations During Treatment 
13.1.1 Treatment Period  
The treatment period consists of 6-7 weeks of concurrent RT and chemotherapy with BMX-001 
followed by 1-2 weeks of BMX-001 (BMX-001 extends to week 8).  
Physical examinations, vital signs (temperature, respiratory rate, blood pressure, and pulse), 
height (screening or baseline only), and weight must be performed at: 
• 
screening 
• 
baseline 
• 
every week from weeks 1-8 
• 
at each SOC visit after completing RT for a period of 1 year 
More frequent examinations may be performed. 


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13.1.2 Physical Exam 
A Physical Examination (PE) will include a general physical examination of major body systems, 
temperature, respiratory rate, blood pressure, heart rate, body weight, and height. 
Height will be measured and documented at screening or baseline only. 
13.1.3 Blood Pressure  
In Phase 1 and the 6 subject safety lead-in in Phase 2, Blood pressure and heart rate will be 
measured pre-dose and then after 5 (±1), 10 (±1), 15 (±2), 30 (±5), 60 (±5), and 120 (±10) 
minutes on the loading dose. It will be checked pre-dose, 30 (±5), and 60 (±5) minutes all other 
days of BMX-001 administration. 
For the Phase 2 study, blood pressure and heart rate will be measured pre-dose, 30 (±5), 60 (±5) 
and 120 (±10) minutes on the loading dose. It will be checked pre-dose, 30 (±5), and 60 (±5) 
minutes post-dose on all other days of BMX-001. 
Blood pressure should be measured with the following standardized techniques: patients should 
be seated in a chair; blood pressure measurement should begin after at least 5 minutes of rest; 
measurements should be taken preferably with a calibrated mercury sphygmomanometer.  
13.1.4 ECG 
ECG will be done for screening purposes and also prior to BMX-001 administration and at 60 
(±15) minutes after dosing on the loading day of BMX-001 and on a BMX-001 administration day 
during Week 1 and Week 4 pre-dose and at 60 (±15) minutes after dosing.   Results will be filed 
in the source for each subject. 
13.1.5 Mucositis 
Mucositis will be clinically assessed weekly during therapy and following therapy at clinic visits 
as listed in the table at the beginning of Section 13. Mucositis will be scored using the CTCAE 
version 4.03 and evaluation will also be done using the FACT-HN and the Oral Mucositis Weekly 
Questinaire-Head+Neck (OMWQ-HN) to be administered on screening and post therapy as listed 
in the table at the beginning of Section 13. 
13.1.6 Xerostomia 
Xerostomia will be assessed using the FACT-HN and the Xerostomia-Related Quality of Life Scale 
(XeQoLS) to be administered at baseline and post therapy as listed in the table at the beginning 
of Section 13. 
Xerostomia will also be assessed by measurement of saliva production at baseline prior to BMX-
001 administration and post therapy as listed in the table at the beginning of Section 13 using 
the following protocol: 
Unstimulated: Clear mouth by spitting excess saliva into a disposable cup. Use a chewing 
motion to encourage saliva production and spit into a plastic cup for 3 minutes. The cup will 
be weighed after 3 minutes and compared to its tare weight to determine the volume of 
saliva produced. 
Stimulated: Clear mouth by spitting excess saliva into a disposable cup. Use a 2x2” square of 
parafilm to chew on and stimulate saliva while spitting all produced saliva into a plastic cup 


Protocol #: BMX-HN-001 
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for 3 minutes. The cup will be weighed after 3 minutes and compared to its tare weight to 
determine the volume of saliva produced. 
Due to institutional practices, subjects may be evaluated for Xerostomia by both the 
radiation oncologist and the medical oncologist. For consistency in reporting adverse events, 
whenever possible the clinical assessments of Xerostomia documented by the radiation 
oncologist will be entered into the CRF. When the subjects are seen by medical oncology 
only, the medical oncologist’s clinical assessment will be used. 
13.2 
Re-treatment Criteria 
Patients must not be experiencing a DLT in order to be retreated. Other dose modifications are 
specified in sections 10.5.1 (cisplatin) and 11.9 (BMX-001). 
13.3 
Follow-up Period 
The follow-up period will consist of an approximately 24-month period following the end of RT 
treatment. 
13.4 
Early Withdrawal of Subject(s) 
13.4.1 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a 
subject from the study at any time based on his/her discretion. Reasons for PI-initiated 
withdrawal may include, but are not limited to the following: 
• 
Adverse events 
• 
Abnormal laboratory values 
• 
Abnormal test procedure results 
• 
Protocol deviation 
• 
Administrative issues 
• 
Disease progression 
• 
Pregnancy 
13.4.2 Follow-up Requirements for Early Withdrawal 
Subjects who prematurely withdraw due to toxicity or progressive disease will be followed for 
six months after a subject is removed from the study. End of study requirements outlined above 
will be conducted. Subjects withdrawn for pregnancy will be followed until the pregnancy is 
ended.  
13.5 
End of Treatment 
The end of treatment will occur when the patient comes off of study for the following reasons: 
completion of all study tests/procedures (approximately 24 months following completion of RT), 
progressive disease, unacceptable toxicity, allergic reaction to chemotherapy, allergic reactions 
to BMX-001, non-compliance with study follow-up, or withdrawal of consent. Patients will be 
followed for a minimum of 30 days after End of Treatment, and also followed for any unresolved 
adverse events considered related to study therapy. Patient death due to progressive disease 
will not be reported as a SAE. 
 


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13.6 
End of Study 
The study will be considered complete once enrollment has been met, follow-up procedures on 
all subjects have been conducted, and data analysis is concluded. The study may also be 
terminated early for any reason by the PI or sponsor. In order to terminate the study, all data 
extraction and analysis must be complete. Therefore, if any articles for publication are derived 
from the current study, they must be submitted and accepted with no further need for 
additional data review prior to termination with the IRB. 
Subjects that are lost to follow-up will be documented in the patient record and in the study 
database. In the study database, the subject will be marked as “Patient Status Unknown,” along 
with a corresponding explanation, if any. This status may also be documented on the “Off Study 
Form” in the study database. 
13.6.1 Early Study Termination 
This study can be terminated at any time for any reason by the PI or sponsor. If this occurs, all 
subjects on study should be notified as soon as possible. Additional procedures and/or follow up 
should occur in accordance with this protocol. 
13.7 
Outcomes Criteria 
13.7.1 Time-to-Event Variables 
Progression-free survival (PFS) is defined as the time between initiation of protocol treatment 
and the first recurrence of disease or death.  
Overall survival will be defined as the time to death from the time of study enrollment.  
13.7.2 Radiographic Response 
Scans will be performed according to standard of care, which commonly would include 
screening or baseline, 3 months ± 2 weeks from the end of radiation therapy, and then 12 
months ± 1 month from the end of radiation therapy. As part of this study protocol, the 12-
month imaging (+/- 1-month post completion of radiation therapy or BMX-001 treatment) will 
be a chest x-ray that is required for research purposes. 
The guidelines and criteria for radiographic response may be based on the RECIST 1.1 criteria 
and apply only to patients receiving definitive intent treatment: 
• 
Complete Response: Disappearance of all enhancing tumor  
• 
Partial Response: Greater than or equal to a 30% reduction in the size (sum of the 
largest perpendicular diameters) for all enhancing lesions taking as reference the 
baseline sum 
• 
Progressive disease: At least a 20% increase in the size (sum of the largest 
perpendicular diameters) for all enhancing lesions, taking as reference the smallest 
sum recorded since the treatment started or the appearance of one or more new 
lesions 
• 
Stable Disease: Evaluations that do not meet criteria for CR, PR or PD  
• 
Not Assessable: Progression has not been documented and one or more sites have 
not been assessed. 


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If RECIST reads are not obtained per SOC per the institution, then imaging reads per the 
institutional standard of practice are acceptable. 
 
Risks of the Chest X-Ray 
Subjects will be exposed to radiation from the required chest X-ray. The amount of radiation 
from a chest X-ray is low — even lower than exposure through natural sources of radiation in 
the environment. The average dose of the chest x-ray is about 0.1 mSv (millisieverts) and the 
average annual effective dose of background radiation is about 3 mSv [61].  
 
13.8 
Quality of Life and Functional Assessments: HRQoL 
The assessments of quality of life and function (XeQoLs, OMWQ-HN, DLQI, FACT-HN, and PRO-
CTCAE HN) will be completed at the following time points: pre-treatment, end of treatment 
(during week 8) and at SOC visits following the end of therapy (this will include, at minimum, 1 
month, 6 and 12 months ± 1 month after treatment). Target windows for data collection will be: 
1) for end of treatment should be collected within 1 month of the last day of radiation therapy; 
and 2) at 6 and 12 months should be collected within ± 1 month of these time-points. However, 
if not possible, data should still be collected outside of these windows and analysis will account 
for the timing of data collection. 
PRO-CTCAE HN: In addition to traditional physician obtained QoL parameters, we will 
incorporate a modification of the PRO-CTCAE which is a new outcome measure recently 
developed by the NCI designed to capture the patient’s self-report of adverse events [60]. A 
subset of items drawn from the PRO-CTCAE system have been aggregated into a head and neck 
specific tool for use in this trial (PRO-CTCAE HN). The PRO-CTCAE HN measure tailored for use in 
this study consists of 25 items that evaluate the presence and/or severity of a range of 
symptoms, as well as the degree to which the symptom/toxicity interferes with usual function. 
Individuals respond to the questionnaire items using a 5-point Likert scale. PRO-CTCAE HN is 
designed to be completed by the patient without assistance from research staff similar to other 
quality of life measures. 
All QoL/functional assessments listed below will be collected from patients at clinic visits via 
case report forms or by electronic data collection at the discretion of each clinical institution. 
All quality of life questionnaires should be completed, even if the patient stops protocol 
treatment.  


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14 
Safety Monitoring and Reporting 
The PI is responsible for the identification and documentation of adverse events and serious 
adverse events, as defined below. PI will review and sign off on all adverse events and problems 
as they occur and will report them to the IRB in accordance with HRPP policies. At each study 
visit, the PI or designee must assess, through non-suggestive inquiries of the subject or 
evaluation of study assessments, whether an AE or SAE has occurred. 
14.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and 
which does not necessarily have a causal relationship with this treatment. For this protocol, the 
definition of AE also includes worsening of any pre-existing medical condition. An AE can there-
fore be any unfavorable and unintended or worsening sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of BMX-001, whether or not 
related to use of the BMX-001. Abnormal laboratory findings without clinical significance (based 
on the PI’s judgment) should not be recorded as AEs, but laboratory value changes that require 
therapy or adjustment in prior therapy are considered adverse events. 
From the time the subject signs the informed consent form through the End of Treatment visit 
(as defined in the section titled End of Treatment), all AEs must be recorded in the subject 
medical record and adverse events case report form. 
AEs will be assessed according to the CTCAE version 4.03. If CTCAE grading does not exist for an 
AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening 
(4), or fatal (5). 
Attribution of AEs will be indicated as follows: 
• 
Definite: The AE is clearly related to the study drug 
• 
Probably: The AE is likely related to the study drug 
• 
Possible: The AE may be related to the study drug 
• 
Unlikely: The AE is doubtfully related to the study drug 
• 
Unrelated: The AE is clearly NOT related to the study drug 
14.1.1 Reporting of AEs 
BioMimetix JV, LLC, should be notified of all treatment-related adverse events on a regular basis 
(to be agreed upon by the study team and BioMimetix JV, LLC).  
14.2 
Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following 
outcomes: 
• 
Fatal 
• 
Life-threatening 
• 
Constitutes a congenital anomaly or birth defect 
• 
A medically significant condition (defined as an event that compromises subject 
safety or may require medical or surgical intervention to prevent one of the three 
outcomes above). 


Protocol #: BMX-HN-001 
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• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant incapacity or substantial disruption to conduct 
normal life functions. 
 
Reports of these should be made to Elizabeth Regan, MD, PhD, at 
Elizabeth.regan@bmxpharma.com, or 303-921-1880 (cell) with the Clinical Trial 
Manager on carbon copy.   
14.2.1 Reporting of SAEs 
Only adverse events that the Sponsor determines to be serious, unanticipated, and related or 
possibly/probably (i.e., more likely than not) related to the research must be reported to the 
appropriate IRB. Those adverse events will be submitted in the applicable IRB and sponsor, 
according the following guidelines: 
• 
Report within 24 hours of learning about any subject’s death that was unanticipated 
and more likely related to the research than unrelated; 
• 
Report within 5 business days of learning about any serious, unanticipated, and 
related or possibly/probably related adverse event; that was more likely related to 
the research than unrelated. 
• 
Report within 10 business days of learning about any other SAE that does not meet 
the above criteria. 
 
The Sponsor must report to the FDA, in an IND safety report, any suspected adverse reaction 
that is both serious and unexpected. Before submitting this report, the sponsor needs to ensure 
that the event meets all three of the definitions contained in the requirement:  
• 
Suspected adverse reaction (i.e., there is a reasonable possibility that the drug 
caused the adverse event) 
• 
Serious  
• 
Unexpected  
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The Sponsor is required to report to the FDA all IND Safety reports in writing within 15 days (7 
days for unexpected fatal or life-threatening suspected adverse reaction). The FDA Form 3500A 
can be found on the FDA website, www.fda.gov. All other adverse events will be reported to the 
FDA in the Annual Report. 
The sponsor is responsible for safety reporting to the FDA and for compliance with all applicable 
laws and regulations pertaining to adverse events. To ensure patient safety each study 
treatment-related serious adverse event will also be reported to BioMimetix JV, LLC, within 24 
hours by the Principal Investigator. Follow-up information on these events shall also be reported 
to BioMimetix JV, LLC, within 24 hours. Follow-up information may include hospital admission 
records, discharge summaries and autopsy reports, where applicable.  
In addition, the Principal Investigator shall also make an accurate report to the reviewing 
Institutional Review Board (IRB) on any serious and unexpected AE per local guidelines.  


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14.3 
External Data and Safety Monitoring Board (DSMB) 
The sponsor and Principal Investigators are responsible for overseeing the safety and efficacy of 
the trial, executing the DSM plan, and complying with all reporting requirements to local and 
federal authorities. Additional oversight will be carried out by an external DSMB. 
An external DSMB will be utilized to monitor the Phase 1/Phase 2 clinical trial of BMX-001. This 
DSMB will be organized to meet requirements of Western IRB, the institutional IRBs, and the 
NCI. We anticipate a charter with a minimum of 3 members, which may include: a radiation 
oncologist, a medical oncologist both with expertise in head and neck cancer, a biostatistician, 
and/or an ethicist or patient advocate. The DSMB will hold an initial meeting to review the final 
protocol before enrollment of the first patient. The responsibilities of the DSMB will be to 
review safety of study procedures, to maintain study integrity, to review adverse events and to 
review efficacy of the outcome data. The DSMB will meet either face to face or by 
teleconference at least semi-annually and on an ad hoc basis as indicated by any adverse events. 
Minutes will be kept of both open and closed meetings of the DSMB. At the end of the study, all 
minutes taken will be available to the clinical trial principal investigators, the NCI, and 
BioMimetix JV, LLC. 
During Phase 2 of the trial, the sponsor will notify the DSMB within 48 hours of any reported 
grade 3- 5 DLT deemed probably or definitely related to BMX-001. 
The DSMB’s responsibilities will include evaluation of treatment outcome for evidence of tumor 
protection by the study drug. If the DSMB determines that there is substantial evidence of 
excess tumor progression in the presence of the study drug, the DSMB will have authority to 
recommend closure of the clinical trial. 
14.4 
Monitoring 
BioMimetix JV, LLC, will be responsible for oversight of monitoring the trial per the trial monitor-
ing plan and will conduct monitoring visits to ensure subject safety and to ensure that the 
protocol is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures, good clinical practice, and applicable regulatory requirements.  
Monitoring visits will be conducted in compliance with FDA regulations (21CFR812), SOPs, and 
GCP/ICH (5.18) guidelines to ensure the integrity of the data reported is accurate and the safety, 
rights, and well-being of the subjects are protected. The clinical trial will be monitored while the 
trial is active and is enrolling and overseeing patients.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or for cause. Every reasonable effort will be 
made to maintain confidentiality during study monitoring. 
14.5 
Audits 
The clinical centers may conduct internal audits to evaluate compliance with the protocol and 
the principles of GCP. The PIs agree to allow auditors direct access to all relevant documents and 
to allocate his/her time and the time of the study team to the auditors in order to discuss 
findings and any relevant issues. 


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The primary purpose of the audit is to verify that the standards for safety of human subjects in 
clinical trials and the quality of data produced by the clinical trial research are met. The audit 
will serve as a quality assurance measure, internal to the institution. Additional goals of such 
audits are to detect both random and systemic errors occurring during the conduct of clinical 
research and to emphasize “best practices” in the research/clinical trials environment. 


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15 
Data Management and Processing 
15.1 
Study Documentation 
Study documentation includes but is not limited to source documents, case report forms, 
monitoring logs, appointment schedules, study team correspondence with sponsors or 
regulatory bodies/committees, and regulatory documents that can be found in the study-
specific regulatory binder, which includes but is not limited to signed protocol and amendments, 
approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory 
certifications, and clinical supplies receipts and distribution records. 
Source documents are original records that contain source data, which is all information in 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. Source documents include but are not limited 
to hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial. When possible, the original record should be retained as the source document. However, a 
photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the 
original document. 
15.2 
Case Report Forms (CRFs) 
The electronic CRF (eCRF) will be the primary data collection document for the study and is 
developed in conjunction with statistical oversight. The CRFs will be updated in a timely manner 
following acquisition of new source data. Only the staff appropriately delegated by the PI are 
permitted to make entries, changes, or corrections in the eCRF. 
An audit trail will be maintained automatically by an electronic CRF management system. All 
users of this system will complete user training, as required or appropriate per regulations. 
15.3 
Data Management Procedures and Data Verification 
Users of the eCRF will have access based on their specific roles in the protocol. 
Completeness of entered data will be checked automatically by the eCRF system, and users will 
be alerted to the presence of data inconsistencies. Additionally, the data management team and 
the statistical team will cross-reference the data to verify accuracy. Missing or implausible data 
will be highlighted for the PI requiring appropriate responses (i.e., confirmation of data, 
correction of data, completion or confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure and will be closed only 
after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to 
the data. 
15.4 
Coding 
All medical terms will be coded using CTCAE v.4.03, which has been harmonized to MedDRA 
(Medical Dictionary for Regulatory Activities) coding. Medication will be coded according to the 
World Health Organization Drug Dictionary. 


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15.5 
Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following 
activities: 
• 
Data clarification and/or resolution; 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs; 
• 
Review of site study records for completeness; 
• 
Shipment of all remaining laboratory samples to the designated laboratories; 
• 
Submitting closure report to IRB. 
15.6 
Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
• 
at least two years after the date on which a New Drug Application is approved by 
the FDA, as an IND is involved; 
• 
at least two years after formal withdrawal of the IND associated with this protocol, 
as an IND is involved; 
• 
per institutional guidelines. 


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16 
Statistical Methods and Data Analysis 
All statistical analysis will be performed under the direction of Christopher Wichman, Ph.D., 
University of Nebraska Medical Center (UNMC). Any data analysis carried out independently by 
the investigator must be approved by the lead statistician before publication or presentation. 
All patients who receive protocol treatment are expected to be included in all statistical 
analyses. In Phase 1, cohorts of 3 patients will be treated starting with dose level #1 and ending 
with dose level #2. Once three patients have undergone treatment without experiencing DLT 
after a monitoring period of four weeks, the dose of the subsequent group of 3 patients will be 
escalated. Phase 1 
16.1.1 Analysis Sets 
All patients who receive protocol treatment are expected to be included in all statistical 
analyses.  
For purposes of determining dose escalation, we expect that all patients will be included in 
analyses with the possible exception of those patients receiving treatment who refuse to return 
for assessment and for whom information concerning toxicity cannot be garnered from other 
sources (e.g., primary care physician, family members, etc). 
For adverse events, overall survival and progression free survival, all patients who receive BMX-
001 will be included in the summaries of adverse events. 
For HRQoL, all patients who receive BMX-001 will be included in the analysis with the possible 
exception of those patients receiving treatment who refuse to return for assessment and for 
whom HRQoL data are not available. 
16.1.2 Patient Demographics and Other Baseline Characteristics 
The clinical and sociodemographic characteristics of all patients treated will be summarized 
using descriptive statistics (e.g., means/standard deviations, percentiles, frequencies). Patient 
characteristics within patient subgroups defined by dose level will also be generated. 
16.1.3 Treatments 
The number of patients treated at each dose level will be summarized. 
16.1.4 Phase 1 Dose Escalation 
16.1.5 Objectives 
16.1.5.1 
Primary Objective 
The primary objective of this Phase 1 study is to determine the maximum tolerated dose 
safety and toxicity profile of BMX-001 administered in conjunction with standard 
radiotherapy and cisplatin among patients with newly diagnosed head and neck cancer. Two 
dose levels were completed: 1) 7 mg/subject and 2) 14 mg/subject followed by maintenance 
doses given twice weekly of 1) 3.5 mg/subject and 2) 7 mg/subject. The toxicity profile will 
be done using the CTCAE version 4.03. 


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16.1.5.2 
MTD 
The MTD has been selected for studying in Phase 2 based on completed Phase 1 human 
trials of BMX-001.  
16.1.5.3 
Secondary Objectives of Phase 1 Study 
Adverse events will be tabulated in a different manner for the manuscript summarizing the 
results of this study, annual reports for the Safety Oversight Committee, and the final report 
included within ClinicalTrials.gov.  
For the manuscript, adverse events that are possibly, probably, and definitely treatment-
related will be summarized. For each type of toxicity, the maximum grade experienced by 
each patient will be summarized with frequency distributions within each treatment group.  
For ClinicalTrials.gov, serious adverse events and other adverse events will be summarized 
separately. These tabulations will reflect the number of patients who experience each type 
of toxicity regardless of grade or attribution.  
CTCAE data will be collected and compared: 
 
1. To assess the effect of BMX-001 in combination with RT and concurrent cisplatin in 
newly diagnosed HNSCC patients on overall survival (OS), progression free survival 
(PFS), and initial response to treatment. 
Kaplan-Meier methods will be used to graphically describe the distribution of overall 
survival (OS) and progression-free survival. OS is defined as the time interval 
between initiation of protocol treatment and death, with overall survival censored 
at last follow-up if the patient remained alive. PFS is defined as the time between 
initiation of protocol treatment and disease progression or death. If the patient 
remains alive without disease progression, then PFS will be censored at last follow-
up. Median OS and PFS, as well as 6- and 12-month estimates of OS and PFS, will be 
estimated from the Kaplan-Meier curve. 
2. To examine the impact on mucositis of BMX-001 in combination with RT and 
concurrent cisplatin in treatment of newly diagnosed patients with locally advanced 
head and neck cancers by evaluating the degree of oral mucositis at 30-39 Gy, 40-49 
Gy, 50-59 Gy, and 60-70 Gy, the duration of oral mucositis, and evaluation of 
mucositis-related patient-reported outcomes. 
The duration of mucositis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be 
descriptively summarized using means and 95% confidence intervals (CIs). The 
evaluation of mucositis-related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 
50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, 
percentages, and 95% CIs. 
3. To examine the impact on xerostomia of BMX-001 in combination with RT and 
concurrent cisplatin by evaluating degree of xerostomia at 30-39 Gy, 40-49 Gy, 50-
59 Gy, and 60-70 Gy, the duration of xerostomia, and evaluation of xerostomia-
related patient-reported outcomes. 
The duration of xerostomia at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be 
descriptively summarized using means and 95% confidence intervals (CIs). The 


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evaluation of xerostomia-related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 
50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, 
percentages, and 95% CIs. 
4. To examine the impact on radiation dermatitis of BMX-001 in combination with RT 
and concurrent cisplatin by evaluating degree of radiation dermatitis at 30-39 Gy, 
40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of radiation dermatitis, and 
evaluation of radiation dermatitis-related patient-reported outcomes. 
The duration of radiation dermatitis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, 
will be descriptively summarized using means and 95% confidence intervals (CIs). 
The evaluation of radiation dermatitis-related patient-reported outcomes at 30-39 
Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using 
frequencies, percentages, and 95% CIs. 
5. To characterize the single-dose and repeated-dose pharmacokinetic profiles of 
BMX-001 when delivered in combination RT and concurrent cisplatin. 
16.1.5.4 
Exploratory Objectives for Phase 1 Study 
The mean change between baseline and each follow-up assessment for HRQoL will 
be descriptively summarized using means and 95% CIs.  
16.2 
Phase 2 
16.2.1 Primary Endpoint 
1) The primary endpoint is incidence of severe oral mucositis (grade 3 and 4). 
 
The incidence rates of severe oral mucositis graded by CTCAE as grade 3 or 4 will be 
descriptively summarized and calculated.    
 
2) The secondary endpoints are: 
1. Median duration (days) of severe oral mucositis 
2. Median time (days) to onset of severe oral mucositis 
3. Incidence of grade >/= 2 Xerostomia at month 1 and 6 post completion 
of RT. 
 
16.2.2 Objectives/Endpoint and Data Analyses 
16.2.2.1 
Primary Objectives for Phase 2 
1. To confirm the safety and tolerability of the MTD of BMX-001 in conjunction 
with RT and concurrent cisplatin in cohort of HNSCC patients. 
The incidence rates of adverse events (AE) will be described without regard 
to causality. AE incidence occurring within each cycle will be described. The 
frequency of overall toxicity, categorized by toxicity grades, will also be 
summarized. Listings of laboratory results collected at baseline and during 
the study will be generated and descriptive statistics summarizing changes 
in laboratory tests over time will be presented. 


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Adverse events will be tabulated in a different manner for the manuscript 
summarizing the results of this study, annual reports for the Safety 
Oversight Committee, and the final report included within ClinicalTrials.gov 
For the manuscript, adverse events that are possibly, probably, and 
definitely treatment-related will be summarized. For each type of toxicity, 
the maximum grade experienced by each patient will be summarized with 
frequency distributions within each treatment group.  
For ClinicalTrials.gov, serious adverse events and other adverse events will 
be summarized separately. These tabulations will reflect the number of 
patients who experience each type of toxicity regardless of grade or 
attribution.  
2. To further explore efficacy based on the impact of BMX-001 on mucositis, 
xerostomia, and radiation dermatitis in treatment of newly diagnosed 
patients with locally advanced head and neck cancers by evaluating the 
degree of these adverse events at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 
Gy, the duration of the adverse events, and evaluation of related patient-
reported outcomes. Comparison against historical controls will be made.  
The duration of mucositis, xerostomia and radiation dermatitis, separately, 
at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively 
summarized using means and 95% confidence intervals (CIs). The evaluation 
of mucositis, xerostomia, and radiation dermatitis, separately, at related 
patient-reported outcomes at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, 
will be descriptively summarized using frequencies, percentages, and 95% 
CIs. 
16.2.2.2 
Secondary Objectives for Phase 2 
1. To assess the efficacy based upon overall survival (OS), median progression 
free survival (PFS), and initial response to treatment 
Kaplan-Meier methods will be used to graphically describe the distribution 
of overall survival (OS) and progression-free survival. OS is defined as the 
time interval between initiation of protocol treatment and death, with 
overall survival censored at last follow-up if the patient remained alive. PFS 
is defined as the time between initiation of protocol treatment and disease 
progression or death. If the patient remains alive without disease 
progression, then PFS will be censored at last follow-up. Median OS and PFS, 
as well as 6- and 12-month estimates of OS and PFS will be estimated from 
the Kaplan-Meier curve. 
2. To assess radiographic response in locally advanced HNSCC patients treated 
with standard RT and cisplatin with BMX-001 at MTD. 
The radiographic response (CR or PR) will be assessed as defined in 12.6.2. 
The radiographic response rate will be tabulated and reported using 
frequencies and 95% confidence intervals. 


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16.2.2.3 
Exploratory Objectives for Phase 2 
1. To further describe patient-reported outcomes of HRQoL in locally 
advanced HNSCC with standard RT, cisplatin, and BMX-001 at the MTD. 
16.2.3 Interim Analysis for Phase 2 
No interim efficacy analyses are planned given the length of time to assess an individual 
patient’s outcome and the expected rapidity of patient accrual. 
16.2.4 Sample Size Calculation for Phase 2 
In this study, patients will receive BMX-001 at the Recommended Phase 2 Dose (RP2D). The 
ultimate goal of this study is to determine whether BMX-001 in combination with standard RT 
and cisplatin treatment is worthy of further investigation. The cohort will be compared with 
historical controls, which will be assessed for quality. 
We will focus on the occurrence and severity of mucositis, xerostomia, and radiation dermatitis 
in this power calculation given that the study is not a randomized study, even though we are 
interested in comparing groups with respect to change in mucositis and xerostomia between 
protocol timepoints.  
We anticipate accruing 48 patients which, for statistical purposes, we assume that 
approximately 40 will have available measurements of mucositis, xerostomia, and radiation 
dermatitis. We use a conservative estimate of a proportion of 0.50 since it results in the widest 
CI. A sample size of 40 produces a two-sided 95% exact confidence interval (Clopper-Pearson) 
with a width equal to 0.324 when the sample proportion is 0.50. 


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routine clinical use. Clin Exper Dermatol 1994; 19(3):210-216. 
 51. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M. Skin 
toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial 
evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of 
life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28(8):1351-57. 
 52. Trzaska SM. Cisplatin. C&EN News June 2005; 83(25). FDA Oncology Tools Approval Summary for 
Cisplatin for Metastatic Ovarian Tumors. Food and Drug Administration, Center for Drug 
Evaluation and Research. 19 December 1978. Archived from the original on 8 February 2008. 
http://web.archive.org/web/20080208232952/http://www.accessdata.fda.gov/scripts/cder/onc
tools/summary.cfm?ID=73. Retrieved 19 Nov 2013. 
 53. Loehrer PJ, Einhorn LH. Drugs five years later. Cisplatin. Ann Intern Med 1984; 100(5):704–13. 
 54. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, Dimanche-
Boitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute 
inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 
2010; 70(19):7514-22.  
 55. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, Dimanche-
Boitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute 
inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 
2010; 70(19):7514-22.  
 56. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, Dimanche-
Boitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute 
inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 
2010; 70(19):7514-22.  
 57. Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS. Germline genetic polymorphisms may 
influence chemotherapy response and disease outcome in osteosarcoma: A pilot study. Cancer 
2012; 118(7):1856–67.  
 58. Levi JA, Aroney RS, Dalley DN. Haemolytic anaemia after cisplatin treatment. Br Med J (Clin Res 
Ed) 1981; 282(6281):2003-4.  
 59. Ross AD, Sheng H, Warner DS, Piantadosi CA, Batinic-Haberle I, Day BJ, Crapo JD. Hemodynamic 
effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species 
specificity. Free Radic Biol Med 2002; 33(12):1657-69. 
 60. Hay JL, Atkinson TM, Reeve BB, Mitchell SA, Mendoza TR, Willis G, Minasian LM, Clauser SB, 
Denicoff A, O'Mara A, Chen A, Bennett AV, Paul DB, Gagne J, Rogak L, Sit L, Viswanath V, Schrag 
D, Basch E; NCI PRO-CTCAE Study Group. Cognitive interviewing of the US National Cancer 
Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE). Qual Life Res. 2014 Feb; 23(1):257-69. 
 61. Mettler FA, et al. "Effective Doses in Radiology and Diagnostic Nuclear Medicine: A 
Catalog," Radiology (July 2008), Vol. 248, pp. 254–63. 
 
 
 


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Appendix A: Functional Assessment of Cancer Therapy – Head and 
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Appendix B: Oral Mucositis Weekly Questionnaire – HN 
 


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Appendix C: Xerostomia-Related Quality of Life Scale 
 
 


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Appendix D: Dermatology Life Quality Index 


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ICF_001.pdf: 
NCT02990468
BMX-HN-001
version 30 Apr 2019


 
 
 
 
Reference Date: Version 4.0, 30 Apr 2019- Phase 2  Page 1 of 16 
Subject Initials 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
TITLE: 
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and 
BMX-001 in Locally Advanced Head and Neck Cancer  
 
PROTOCOL NO.: 
BMX-HN-001 
 
WIRB® Protocol #20161850 
 
SPONSOR: 
BioMimetix JV, LLC 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State, Zip Code 
 
Country 
 
STUDY-RELATED  
Name 
PHONE NUMBER(S): 
Phone Number(s) (24-hour number required) 
 
 
You are being asked to be in a research study. The purpose of this consent form is to help you 
decide if you want to be in the research study. 
 
You should not join this research study until all of your questions are answered. 
 
PURPOSE OF THE STUDY 
You are being asked to take part in this research study because you have head and neck cancer. 
Research studies are voluntary and include only people who choose to take part. Please read this 
consent form carefully and take your time making your decision. As your study doctor or study 
staff discusses this consent form with you, please ask him/her to explain any words or 
information that you do not clearly understand. We encourage you to talk with your family and 
friends before you decide to take part in this research study. The nature of the study, risks, 
inconveniences, discomforts, and other important information about the study are listed in this 
document. 
 
Please tell the study doctor or study staff if you are taking part in another research study. 
 
 


 
 
 
 
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Subject Initials 
 
 
 
 
Concise Summary 
The purpose of this study is to find out what effects, (good or bad), an investigational drug 
called BMX-001 may have on patients with head and neck cancers when given in combination 
with cisplatin and radiation therapy. The word “investigational” means the study drug is still 
being tested in research studies and is not approved by the U.S. Food and Drug Administration 
(FDA). It is thought BMX-001 may reduce the bad side effects of radiation therapy to the skin 
and inside of the mouth of the head and neck region, although there is no proof of this yet.  In 
this study, all subjects will receive investigational agent BMX-001 with radiation therapy and 
cisplatin. The study will also collect information on your quality of life, side effects of the 
treatment, and survival. 
BMX-001 is injected under the skin. The first dose is given a couple of days before radiation 
therapy (RT) starts, and BMX-001 is given for eight weeks.  There are risks to this study drug 
that are described in this document.  Some risks include irritation at the injection site, feeling 
tired, and a temporary drop in blood pressure.   
If you are interested in learning more about this study, please continue reading below. 
 
 
[Principal Investigator name] will conduct the study and it is funded by BioMimetix JV, LLC, 
the sponsor of this study. BioMimetix JV, LLC, will pay [institution/site name] to perform this 
research, and these funds may reimburse part of [Principal Investigator name] and his/her 
research team’s salaries. The funding coming from BioMimetix JV, LLC is in part supported by 
a Small Business Innovation Grant funded by the National Cancer Institute to BioMimetix JV, 
LLC. 
 
WHO WILL BE MY DOCTOR ON THIS STUDY? 
If you decide to participate, [Principal Investigator name] or one of the other doctors at 
[institution/site name] will be your doctor for the study. If you choose, your study doctor or a 
member of the research team can notify your regular health care provider about your 
participation in this study.  
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to find out the effect of the investigational study drug (BMX-001) in 
combination with radiation therapy and cisplatin. The word “investigational” means the study 
drug is still being tested in research studies and is not approved by the U.S. Food and Drug 
Administration (FDA). BMX-001 is thought to reduce the toxicities (bad side effects) of 
radiation therapy to the skin and mucosa (inside of the mouth) of the head and neck region. 
BMX-001 is a new class of compound that would be termed "a redox-active metalloporphyrin."  
This drug was designed to mimic the body's most powerful antioxidant enzymes and is a potent 
anti-inflammatory that acts by blocking multiple steps in the inflammatory cascade. By 
inhibiting the inflammatory cascade BMX-001 is expected to protect normal tissues from the 
inflammatory side-effects of radiation and chemotherapy while at the same time acting as an 
antioxidant that will have an inhibitory effect on the growth of tumor.   
 
In addition to this study, there are additional studies evaluating this drug with radiation for other 
types of cancers. Although this compound may be effective in blocking radiation related damage 
to your skin and mucosal surfaces inside your mouth and throat, providing direct medical benefit 


 
 
 
 
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Subject Initials 
 
to you is not the main purpose of this study. The main purpose of this study is to learn about the 
safety of the drug. Please carefully read the sections on risk and benefits below. 
 
This is a Phase 2 study.   
 
Phase 2 will continue to evaluate safety and tolerability of the study drug (BMX-001) in 
combination with standard radiation therapy and cisplatin for patients with head and neck cancer. 
It will also explore how the study drug works to improve the side effects of treatment including 
sore mouth/throat, skin changes and dry mouth.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 48 people will take part in Phase 2 of this study at up to five institutions in the United 
States.  
 
WHAT IS INVOLVED IN THIS STUDY? 
Screening 
 
If you agree to be in this study, you will be asked to sign and date this consent form. You will 
then need to complete the following tests and procedures to make sure that you are eligible: 
§ Vital signs, including blood pressure and heart rate 
§ Past Medical History and physical exam 
§ An Electrocardiogram (ECG) 
§ As part of the standard of care for your cancer, you will receive examinations of your 
throat and voice box (larynx) done with a mirror and/or flexible lighted tube inserted 
through your mouth. Findings from this examination will be included in the research 
database for this clinical study. 
§ As part of the standard of care for your cancer, you will have imaging studies done of 
your head and neck using CT (computed tomography) and/or MRI (magnetic resonance 
imaging) and/or a PET (positron emission tomography) scans, which is a computerized 
image that looks at the activity of tumor cells in your entire body. Findings from these 
imaging studies will be included in the research database for this clinical study. 
§ Blood draw (by needlestick) for hematology (blood counts), blood chemistry tests, and a 
blood test that measures how long it takes your blood to clot. 
§ Blood pregnancy test, if you are female of childbearing potential, will be done if you are 
enrolled in the study 48 hours prior to study drug administration 
§ Review of current medications 
§ Review of medical and demographic information 
§ An evaluation of your ability to chew and swallow  
§ You will be asked about your diet, eating, and speech 
§ Evaluation of your ability to carry out daily activities 
§ Measurement of your saliva production, this is a quick test to determine how much saliva 
your body is producing 
§ Questionnaires 
 
After completion of the screening process, the doctor will determine whether you are eligible to 
participate in the treatment part of the study. If you are eligible and you choose to participate, 
you will be enrolled in the study. If you do not meet the eligibility requirements, you cannot take 


 
 
 
 
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Subject Initials 
 
part in this study, in which case your doctor will inform you of other options that are available to 
you. 
 
During the Study:  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures. Some are part of regular cancer care.  
 
Weekly during treatment: 
 
• 
A physical examination 
• 
Information regarding medications you are taking 
• 
Blood tests (about 3 teaspoons of blood will be taken from your vein) 
• 
Evaluation of any side effects from treatment you may be having 
 
During weeks 1 and 4 of treatment, you will have an ECG done before and after (at about 60 
minutes) receiving the study drug.  During the last week of treatment, we will ask you the 
questionnaires again.   
 
During treatment, if your study doctor recommends: 
 
• 
A whole body PET/CT 
• 
CT scans, MRI, or PET/CT of your neck 
• 
A biopsy to check for recurrence of the cancer 
• 
Evaluation of any side effects from treatment more often than weekly, if needed 
 
You will need these tests and procedures in follow-up visits:  
These tests and procedures are being done to see how you and your cancer was affected by the 
treatment you received as well as evaluation of any treatment related toxicity. These tests and 
procedures are part of regular cancer care. 
 
At about 1 month after you finish treatment: 
 
• 
A physical examination  
• 
Questionnaires 
• 
Information regarding medications you are taking 
• 
Evaluation of your ability to carry out daily activities 
• 
Blood tests (about 3 teaspoons of blood will be taken from your vein)  
• 
Evaluation of any side effects from treatment you may be having 
 
At about six months and one year after you finish treatment: 
 
• 
A physical examination  
• 
Questionnaires 
• 
Information regarding medications you are taking 
• 
Evaluation of your ability to carry out daily activities 
• 
Blood tests (about 3 teaspoons of blood will be taken from your vein) 
• 
Evaluation of any side effects from treatment you may be having 
 


 
 
 
 
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Approximately one year after finishing treatment, you will have a chest x-ray completed as part 
of this study.     When you complete the study, we will continue to contact you every couple of 
months or you will be followed through your Electronic Medical Record (EMR) to see how you 
are doing for up to two years.      
 
The tests during screening and throughout the study are explained in more detail below: 
 
Blood Tests: In total, approximately 4 teaspoons (20 mL) of blood will be drawn from your arm 
by a needlestick for the evaluations before starting the study drug during the screening period. 
These blood tests done at screening will include a complete blood count (CBC), blood chemistry 
(CMP) and tests of how well your blood clots (PT/aPTT). During the course of the study, 
complete blood count (CBC) tests and blood chemistry (CMP) tests will be drawn 
(approximately 3 teaspoons) while you are receiving radiation therapy beginning at Week 1. 
Following the cessation of radiation therapy, complete blood count (CBC) and blood chemistry 
(CMP) tests will be drawn (3 teaspoons) at approximately one month, six and twelve months 
after radiation therapy.  
 
For women of childbearing potential, a blood test to rule out pregnancy will be done during the 
screening period within 48 hours prior to starting the study drug. Approximately 1 teaspoon of 
blood will be taken to perform this test. 
 
In total, approximately 34 teaspoons (170 mL) of blood may be drawn during the study period 
for standard clinical blood tests such as CBC and CMP over a 1-year period. 
 
Evaluation of Oral Mucositis: Mucositis is painful inflammation and ulceration of mucous 
membranes. Mucositis is typically a side effect of chemotherapy and radiotherapy treatment for 
cancer. This questionnaire will be completed at every visit. 
 
Electrocardiogram (ECG): ECG is a diagnostic tool that is routinely used to assess the electrical 
and muscular functions of the heart. This will be done at the screening visit as well as on the first 
day you receive the study drug and during weeks 1 and 4, before and about 60 minutes after the 
initial study drug injection. 
 
Questionnaires: Quality of life will be assessed by using patient report outcomes (PROs). PROs 
refer to the subjective report of symptoms, concerns, and feelings. This will be evaluated using 
questionnaires. These questionnaires will ask questions about your overall well-being, mood, 
thoughts, feelings, physical function and thinking. 
 
Additional tests may be done at the discretion of your physician as part of your regular care 
throughout the study. These exams and tests will be done to monitor the effects of study drugs. 
 
Study Procedures 
After screening, the treatment period of the study will consist of 6-7 weeks of radiotherapy and 
cisplatin with BMX-001, followed by an additional 1-2 weeks of BMX-001. After completion of 
treatment for your cancer, no further administration of BMX-001 will be given. All subjects in 
the study will receive the study drug. 
 


 
 
 
 
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You should contact your study doctor at any time to let him or her know of any bad side effects 
that you might be having. 
 
HOW LONG WILL I BE IN THIS STUDY? 
You will receive the study drug, BMX-001 under the skin starting up to 4 days before you start 
radiation therapy and then 2 times each week for the approximately 6-7 weeks of your radiation 
therapy.  BMX-001 injections are given before, during and after radiation therapy for a total of 
17 planned doses.  You will then be followed on this study for approximately two years. 
Thereafter, you will continue to receive routine care as determined by your treating physician. 
Patients can receive study treatment as long as there is no evidence of disease progression or 
unacceptable toxicity. The study doctor may also take you off the study if new scientific 
developments occur that indicate the treatment is not in your best interest, or he/she feels that 
this treatment is no longer in your best interest. 
 
We will tell you about new information that may affect your health, welfare, or willingness to 
stay in this study. 
 
You can choose to stop participating at any time without penalty or loss of any benefits to which 
you are entitled. However, if you decide to stop participating in the study, we encourage you to 
talk to your doctor first. 
 
The initial study visit and the study visits at the end of your radiation therapy and at 1, 6 and 12 
months post radiation therapy will take approximately 2 additional hours to fill out all of the 
questionnaires. Your other clinical visits during radiation/chemotherapy will be standard of care.  
 
WHAT ARE THE RISKS OF THE STUDY? 
Side effects of study drugs and procedures may be mild or they may severe enough to be life 
threatening. They may resolve (stop) after you stop the study drug or procedure or they may 
continue.  
 
Adding BMX-001 to standard of care therapy may interfere with the effectiveness of radiation or 
chemotherapy. 
 
As a result of your participation in this study, you are at risk for the following side effects: 
 
BMX-001 may cause some, all or none of the side-effects listed below. BMX-001 has only been 
given to animals before. Side effects are dose-dependent and the relatively low doses of this drug 
planned in this study have not been associated with side effects in animals other than those 
related to the color of the injected drug. 
 
The most common side effects (expected to occur in more than 30% of subjects) are: 
 
• 
Red to brown discoloration of the skin at the injection site which may take up to several 
weeks to resolve 
• 
Irritation at the site of the injection of the drug under the skin 
• 
Transient tachycardia (fast heart beat) after receiving the study drug  
 
Less common side effects (expected to occur in 10-30% of subjects) are: 


 
 
 
 
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• Pain at the site of the injections of the drug under the skin 
• Local histamine release which could be caused by the study drug. This could cause 
pruritus (itching), erythema (redness), edema (swelling), urticaria (welts).  This is 
expected to resolve within a couple of hours of injection.   
 
Rare side effects (expected to occur in less than 10% of subjects) are: 
• Temporary hypotension (low blood pressure) 
• Malaise or “not feeling well” for a few hours 
• Prolongation of the QT interval after the loading dose.  This is a condition in which your 
heart muscle takes slightly longer than normal to recharge between beats. This can be 
seen on an ECG, and is called a prolonged QT interval. We will monitor this by 
performing ECGs before and after study drug administration the first day you receive the 
drug and then twice (or more if indicated by your doctor) during BMX-001 treatment.  
Many drugs are known to cause this.  For more information about this please discuss with 
your study doctor.   
 
After discharge, you should be alert for potential symptoms of low blood pressure, which may 
include dizziness, fainting, lightheadedness, blurry vision, weakness, nausea, vomiting. These 
symptoms may occur when you change from lying down or sitting to a standing position. If they 
occur, you should lie down, elevate your feet and contact your health care provider if these 
symptoms persist. 
 
An additional possible side effect is: 
• Light-activated skin rash in response to sun exposure 
• Red to dark color of urine 
• It is also possible that previously unobserved and unexpected side effects could occur. 
 
Possible Side Effects Related to Cisplatin: The cisplatin you will receive is considered 
standard of care for your tumor. The amount of cisplatin you will receive by participating in this 
study is the same as for patients with the same disease who are not taking part in this study. The 
cisplatin may be administered either every 3 weeks or weekly, both of which are accepted 
approaches. 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Anemia, which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Kidney damage, which may cause swelling, may require dialysis 
• Hearing decrease, including ringing in ears 
• Change in taste 
 


 
 
 
 
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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, from 4 to 20 may have: 
• Allergic reaction, which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Confusion 
• Difficulty with balance 
• Numbness in the fingers and toes 
• Low blood pressure 
• Low magnesium in the blood, which may cause heart beat irregularities that are possible 
life threatening 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, 3 or fewer may have: 
• Cancer of bone marrow later in life caused by chemotherapy  
• Seizure 
 
Possible Side Effects of Radiation Therapy to the Head and Neck: The radiation you will 
receive is considered standard of care for your tumor. The amount of radiation you will receive 
by participating in this study is the same as for patients with the same disease who are not taking 
part in this study.  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, more than 20 and up to 100 may have: 
• Sores in the mouth and/or throat which can be painful and make it very difficult to 
chew and or swallow foods 
• Mouth dryness or changes in taste and/or smell that may be permanent 
• Thick saliva 
• Hoarseness 
• Tanning or redness and/or irritation of the skin in the head and neck area being 
treated with radiation 
• Ear pain and/or pressure 
• Fatigue 
• Weight loss 
• Permanent hair loss in the area treated with radiation (face, chin, neck) 
• Loss of teeth, or cavities in the teeth, if strict dental care is not followed and/or 
hypersensitivity of teeth 
 
 


 
 
 
 
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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving radiation therapy, from 4 to 20 may have: 
• Decrease in function of the thyroid gland that may require you to take thyroid 
replacement medicine to prevent you from feeling tired or sleepy 
• Serious damage to the jawbone, voice box, skin, or other parts of the head and neck 
that may require a major operation to correct and, rarely, can even be life 
threatening 
• Temporary pain or scarring around nerves in the shoulder that could cause 
numbness and/or weakness 
• Breathing problems 
• Difficulty with swallowing and eating for which you might need a long term or 
permanent feeding tube; possibility of inhaling food and/or liquids into the lungs – 
which could also result in pneumonia. This side effect is more likely for patients 
receiving radiation and cisplatin (Group 1). 
• Serious ear infections and/or hearing loss 
• Loss of hearing 
 
Use of special techniques to visualize your tumor and normal tissue, called Image Guided 
Radiation Therapy or IGRT may lead to improved accuracy of radiation treatment compared to 
regular radiation therapy and eventually, that will be more useful against cancer. At this time, 
however, there is no proof that using this technique is more useful against cancer than regular 
radiation treatment without this technique. The dose from these x-ray images is much smaller 
than the dose used to treat your cancer. However, this dose will cover a somewhat larger region 
and can spill over to healthy tissues and organs that are not affected by your disease. There is a 
small risk that the dose from these x-ray images can be harmful, and every effort will be made to 
minimize this dose to healthy tissues. In this effort, it is important that we have your full 
cooperation in maintaining your position during treatment. In order to help you stay in position, 
your doctor will use a special device, sometimes called an immobilization mask. The mask is 
plastic mesh formed to the head and shoulder area to help stabilize your position during 
treatment so as to ensure accuracy of radiation treatments daily. 
 
Blood Draws: The collecting of blood samples to monitor your health throughout this study may 
cause mild discomfort or pain from the needle puncture and possible bruising or mild bleeding. 
The risk of infection is slight and will be further reduced by keeping the puncture site clean and 
dry. 
 
Drug and Food Interactions: For your safety, you must tell the study doctor or nurse about all 
the prescribed medical food and drugs, herbal products, over-the-counter (OTC) drugs, vitamins 
and natural remedies that you are taking before you start the study and before taking any of these 
products while you are on the study. 
 
A CT Scan exposes you to radiation.  This is considered standard of care as part of your 
treatment.  Exposure to radiation adds up over a lifetime. The total dose of radiation from a CT 
scan is about three times the amount of radiation you would normally be exposed to in one year 
("background radiation"). The amount of radiation can vary depending on the part of the body 
that is being examined. If you have more procedures that expose you to radiation, your risk will 
go up. Risks of harm include getting a cancer, or changes to your genes. Your risk of harm may 
be as high as 1 in 1,000. Your study doctor can discuss this with you in more detail.   


 
 
 
 
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A Positron Emission Tomography (PET) scan exposes you to radiation.   This is considered 
standard of care as part of your treatment.  Exposure to radiation adds up over a lifetime. The 
total dose of radiation from a PET scan is usually around three times the amount of radiation you 
would normally be exposed to in one year (“background radiation”). The additional exposure 
from a PET scan largely depends on what part of your body is being examined. If you have more 
procedures that expose you to radiation, your risk will go up. Risks of harm may include getting 
a new cancer or changes in your genes. Your risk of harm may be as high as 1 in 1000. If you 
have an injection into a vein for the PET scan, the needle could cause pain, bleeding, bruising, or 
infection. The contrast media ("dye") that is injected into the vein can cause an allergic reaction 
bad enough to cause death. Your study doctor can discuss this with you in more detail. 
 
The MRI may mean some added discomfort for you.   This is considered standard of care as part 
of your treatment.  In particular, you may be bothered by feelings of claustrophobia and by the 
loud banging noise during the MRI. Temporary hearing loss has been reported from this loud 
noise. You may be asked to wear ear protection. At some time during the test, you may be asked 
to hold your breath for a while, which can be uncomfortable. Because potential risks to a fetus 
from a MRI are unknown, pregnant women must not have a MRI.  
 
Chest X-ray:  You will be exposed to additional radiation from the required chest X-ray which 
is a part of this study.  The amount of radiation you will receive from a chest X-ray is low — 
even lower than exposure through natural sources of radiation in the environment.  The average 
dose of the chest x-ray is about 0.1 mSv (millisieverts) and the average annual effective dose of 
background radiation is about 3 mSv.   
 
Quality of Life Studies: We want to know your view of how your life has been affected by 
cancer and its treatment. This “Quality of life” study looks at how you are feeling physically and 
emotionally during your cancer treatment. It also looks at how you are able to carry out your 
day-to-day activities. 
 
This information will help doctors better understand how patients feel during treatments and 
what effects the medicines are having. In the future, this information may help patients and 
doctors as they decide which medicines to use to treat cancer. 
 
You will be asked to complete 6 questionnaires at 4 time points: before treatment, at the end of 
treatment, and at approximately 6, and 12 months after you finish treatment. It takes about 15-20 
minutes to fill out these questionnaires.  
 
If any questions make you feel uncomfortable, you may skip those questions and not give an 
answer. 
 
If you decide to take part in this study, the only thing you will be asked to do is fill out the 6 
questionnaires. You may change your mind about completing the questionnaires at any time. 
 
Confidentiality: There is also the potential risk of loss of confidentiality. Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed. Some of the 
questions we will ask you as part of this study may make you feel uncomfortable. You may 


 
 
 
 
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Subject Initials 
 
refuse to answer any of the questions and you may take a break at any time during the study. You 
may stop your participation in this study at any time. 
 
There may be risks, discomforts, drug interactions or side effects that are not yet known. 
 
For Those of Reproductive Potential 
Female 
 
Being a part of this study while pregnant may expose the unborn child to significant risks, some 
of which may be currently unforeseeable. Therefore, pregnant women will be excluded from the 
study. If you are a woman of childbearing potential, a blood pregnancy test will be done (using 1 
teaspoon of blood drawn from a vein by needle-stick), and it must be negative before you can 
continue in this study. If sexually active, you must agree to use appropriate contraceptive 
measures for the duration of the study and for 12 months afterwards. Medically acceptable 
contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) 
approved hormonal contraceptives (such as birth control pills, patches, implants or injections), 
(3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an 
intrauterine device (IUD). Contraceptive measures such as Plan B(TM), sold for emergency use 
after unprotected sex, are not acceptable methods for routine use. If you do become pregnant 
during this study or if you have unprotected sex, you must inform your study physician 
immediately. 
 
Women who are pregnant or nursing a child may not take part in this study. Before entering the 
study, you and your study doctor must agree on the method of birth control you will use during 
the entire study. If you think that you have gotten pregnant during the study, you must tell your 
study doctor immediately. Pregnant women will be taken out of the study and followed until the 
pregnancy has ended. 
 
There may be side effects that are not known at this time. 
 
Male 
Your participation in this research may damage your sperm, which could cause harm to a child 
that you may father while on this study. Such harm may be currently unforeseeable. If you are 
sexually active, you must agree to use a medically acceptable form of birth control in order to be 
in this study and for 12 months afterward. Medically acceptable contraceptives include: (1) 
surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide. 
Contraceptive measures such as Plan B(TM), sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. You should inform your partner of the potential for harm to 
an unborn child. She should know that if pregnancy occurs, you will need to report it to the study 
doctor, and she should promptly notify her doctor. 
 
There may be side effects that are not known at this time. 
 
WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
Study records that identify you will be kept confidential as required by law. Federal Privacy 
Regulations provide safeguards for privacy, security, and authorized access. Except when 
required by law, or for your care, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records disclosed 


 
 
 
 
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outside of [institution/site name] with the exception that your date of birth and dates of service 
may be recorded. For all other records disclosed outside of [institution/site name], you will be 
assigned a unique code number. The key to the unique code number will be maintained 
electronically on a secure network, which is accessible only to key personnel for the study and is 
password protected. As part of the study, [Principal Investigator name] and his or her study team 
will report the results of your study-related tests to the sponsor, BioMimetix JV, LLC. “Sponsor” 
includes any persons or companies that are contracted by the sponsor to have access to the research 
information during and after the study. 
 
Study-related tests would include laboratory tests such as your blood counts and tests to measure 
the function of your liver and kidneys, neurological tests, and radiographic studies. Research 
records, records about phone calls made as part of this research, and records about your study visits 
may also be shared with the sponsor. In addition, your records may be also reviewed in order to 
meet federal or state regulations.  
 
A Data Safety Monitoring Board (DSMB) will be utilized to review this study. The purpose of 
this board is to review safety of study procedures, to maintain study integrity, to review adverse 
events and to review the results of the data from the study. 
 
Reviewers may include representatives from the Food and Drug Administration, The U.S. Food 
and Drug Administration (FDA), Department of Health and Human Services (DHHS) agencies, 
Governmental agencies in other countries, representatives of BioMimetix JV, LLC, the DSMB, 
the Western Institutional Review Board and the principal investigators of all participating 
institutions. If any of these groups review your research record, they may also need to review 
your entire medical record. This information may be needed to do the research, to study the 
results, and to see if the research was done right.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• Qualified representatives of the pharmaceutical collaborator 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
The study results may be retained in your research record indefinitely. Any research information 
in your medical record will also be kept indefinitely. 
 
While the information and data resulting from this study may be presented at scientific meetings 
or published in a scientific journal, your identity will not be revealed. 
 
You do not have to give permission to use and give out my health information, but then you will 
not be able to be in this research study. There is no expiration date for the use of this research 
information. 


 
 
 
 
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You may withdraw or take away your permission to use and disclose your health information at 
any time. You do this by sending written notice to the study doctor. If you withdraw your 
permission, you will not be able to stay in this study. 
 
You may have the opportunity to review or copy your information, but only after the research is 
over.  
 
When you withdraw your permission, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given to 
others.  
 
There is a risk that your information will be given to others without your permission. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
This drug has not previously been given to human subjects and therefore it is unknown whether 
or not it will benefit you by reducing the side effects of treatment.  Potential benefits may include 
protection against mucositis and xerostomia caused by radiation therapy.   We hope that in the 
future the information learned from this study will benefit other people with your condition. 
 
During this research project, new information regarding the risks and benefits of the study may 
become known to the investigators. If this occurs, they will tell you about this new information. 
New information may show that you should no longer participate in the research. New 
information may also require you to sign a new consent form. If this occurs, the persons 
supervising the research will stop your participation in it. In either case, you will be offered all 
available care that suits your needs and medical conditions. 
 
WHAT OTHER OPTIONS ARE THERE? 
Instead of being in this study, you have these options: 
 
• You could choose to receive alternative investigational drugs. 
• You could choose to receive the same radiation and chemotherapy as in this study or 
other standard therapy for this disease without BMX-001. 
• You could choose to receive the standard therapy for this disease. 
• You could choose to receive no therapy at this time and receive care to help you feel 
more comfortable. If you choose this option, you may reconsider at any time, and this 
decision will in no way affect the regular care that you receive. 
 
Please talk to your doctor about these and other options. 
 
WHAT ARE THE COSTS? 
There will be no additional costs to you as a result of being in this study. However, routine 
medical care for your condition (care you would have received whether or not you were in this 
study) will be charged to you or your insurance company. You may wish to contact your 
insurance company to discuss this further. In order to make sure that tests and studies done solely 
for research purposes are charged correctly, we will carefully monitor your charges as long as 
you are participating in this study. These tests and studies are not a part of routine care, and 
people who are not part of the study do not usually have them performed. Please ask [Principal 


 
 
 
 
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Subject Initials 
 
Investigator] if you would like to know more about which tests and studies are being done solely 
for research purposes. 
 
BMX-001 is provided free of charge by BioMimetix, JV LLC while you are on study. Cisplatin 
is commercially available and will not be supplied free of charge. Radiation therapy is standard 
of care and will not be supplied free of charge. 
The study sponsor BioMimetix has agreed to pay for services and procedures that are done solely 
for research purposes.  Please talk with the PI/study team about the specific services and 
procedures that the sponsor will pay for, and the ones for which you or your insurance will be 
responsible. 
 
The following are research-related costs and will not be charged to you or your insurance: 
 
1. Blood draw (by needlestick) for a test to check how quickly your blood clots 
2. ECGs – at screening and three on the loading dose day of BMX-001, followed by two 
more during the BMX-001 treatment period.  
3. The chest x-ray at approximately 12 months following completion of treatment.  If the x-
ray is clinically indicated and ordered as standard of care it will be billed to your 
insurance. If the scan is completed as a required study procedure, the sponsor 
BioMimetix will pay for the scan. 
 
If you do not sign this consent form, you will continue to receive care, but not as a part of this 
study. 
 
WHAT ABOUT COMPENSATION? 
You will receive no payment for taking part in this study. 
 
WHAT ABOUT RESEARCH RELATED INJURIES? 
Immediate necessary medical care is available at [Institution/Site name] in the event that you are 
injured as a result of your participation in this research study. However, there is no commitment 
by [Institution/Site name], BioMimetix, JV LLC, or your physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury. 
 
For questions about the study or research-related injury, contact [Principal Investigator] at 
[phone number] during regular business hours and at [24 hour phone number] after hours and on 
weekends and holidays. 
 
You have not waived any of your rights to legal recourse in the event of research-related harm.   
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW 
FROM THE STUDY? 
Your participation in this study is voluntary. You may decide not to participate or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which 
you are entitled. If you withdraw from the study, no new data about you will be collected for 
study purposes unless the data concern an adverse event (a bad effect) related to the study. If 
such an adverse event occurs, we may need to review your entire medical record. All data that 
have already been collected for study purposes, and any new information about an adverse event 
related to the study, will be sent to the study sponsor. 


 
 
 
 
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Your decision not to participate or to withdraw from the study will not involve any penalty or 
loss of benefits to which you are entitled, and will not affect your access to health care at 
[institution/site name]. If you do decide to withdraw from the study, we ask that you contact 
[Principal investigator] in writing and let him/her know that you are withdrawing from the study. 
His/her mailing address is [mailing address]. 
 
We will tell you about new information that may affect your health, welfare, or willingness to 
stay in this study. 
 
Your doctor may decide to take you off this study if your condition gets worse, if you have 
serious side effects, or if your study doctor determines that it is no longer in your best interest to 
continue. The sponsor or regulatory agencies may stop this study at any time without your 
consent. A reason why this might occur includes new identification of an unexpected problem 
with the study drug. If this occurs, you will be notified and your study doctor will discuss other 
options with you. 
 
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures done so that you leave the study safely. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have problems, concerns, 
questions, complaints or suggestions about the research, contact [Principal Investigator] at 
[phone number] during regular business hours and at [24-hour phone number] after hours and on 
weekends and holidays. 
 
For questions about your rights as a research participant, or to discuss problems, concerns, 
complaints or suggestions related to the research, or to obtain information or offer input about 
the research, contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington 98374-2115 
Telephone: 1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times. However, you may contact WIRB if the research staff cannot be reached or if 
you wish to talk to someone other than the research staff. 
 
CONSENT 
I have read this consent form (or it has been read to me). All my questions about the study and 
my part in it have been answered. I freely consent to be in this research study. 
 
I authorize the release of my medical and research records for the purpose of this study. 
By signing this consent form, I have not given up any of my legal rights. 


 
 
 
 
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Subject Name (printed) 
 
CONSENT SIGNATURES: 
 
 
 
 
 
 
Signature of Subject  
Date 
 
 
• I have explained the study to the extent compatible with the subject’s understanding, and 
the subject has agreed to be in the study. 
 
 
 
 
 
 
Signature of Person Conducting Consent Discussion 
Date