protocol # bmx-hn-001 a phase
untitled h2

Sponsor: BioMimetix JV, LLC
Funding Source: National Cancer Institute - SBIR Contract to BioMimetix JV, LLC
NCT02990468 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
signature page sponsor signature page
untitled h2

| BMX-HN-001       |                |
|------------------|----------------|
| Protocol number: |                |
| Version:         | 6.0            |
| Protocol Title:  | April 30, 2019 |
| Version Date:    |                |
| Approved by:     |                |  
A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-
01 in Locally Advanced Head and Neck Cancer  
  
  
Shayne Gad, PhD
Authorized Signature on behalf of IND Sponsor  
  
1
signature page sponsor signature page
1 signature page sponsor signature

| Protocol number:   | BMX-HN-001     |
|--------------------|----------------|
| Version:           | 6.0            |
| Protocol Title:    | A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX001 in Locally Advanced Head and Neck Cancer                |
| Version Date:      | April 30, 2019 |
| Approved by:       |                |
signature page sponsor signature page
principal investigator signature page

Protocol number: BMX-HN-001  
| Version:   | 6.0   |
|------------|-------|  
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.  
| Protocol Title:   | A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX001 in Locally Advanced Head and Neck Cancer   |
|-------------------|---|  
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

| Table of Contents                                                                                                                                                      |                                                                                                                                                                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1 Signature Page                                                                                                                                                       |                                                                                                                                                                |
| Table of Contents ...................................................................................................................................................4 |                                                                                                                                                                |
| 2 List of Abbreviations                                                                                                                                                |                                                                                                                                                                |
| Schema of Clinical Trial .                                                                                                                                             |                                                                                                                                                                |
| 3                                                                                                                                                                      |                                                                                                                                                                |
| 4 Introduction                                                                                                                                                         |                                                                                                                                                                |
| Head and Neck Cancer                                                                                                                                                   |                                                                                                                                                                |
| 4.1                                                                                                                                                                    |                                                                                                                                                                |
| 4.1.1                                                                                                                                                                  | Disease                                                                                                                                                        |
| 4.1.2                                                                                                                                                                  | Radiation-induced Damage                                                                                                                                       |
| 4.2                                                                                                                                                                    | BMX-001                                                                                                                                                        |
| 4.3                                                                                                                                                                    | Study Design .                                                                                                                                                 |
| 4.3.1                                                                                                                                                                  | Phase 1- Completed                                                                                                                                             |
| 4.3.2                                                                                                                                                                  | Phase 2                                                                                                                                                        |
| 4.4                                                                                                                                                                    | Rationale                                                                                                                                                      |
| 4.4.1                                                                                                                                                                  | Study Rationale ........................................................................................................................................16     |
| 4.4.2                                                                                                                                                                  | Rationale for Selection of Dose, Regimen, and Treatment Duration ............................................16                                                |
| Quality of Life and Function Assessments ...............................................................................................................16             |                                                                                                                                                                |
| 4.5                                                                                                                                                                    |                                                                                                                                                                |
| 5 Objectives                                                                                                                                                           |                                                                                                                                                                |
| 5.1                                                                                                                                                                    | Phase 1                                                                                                                                                        |
| 5.1.1                                                                                                                                                                  | Primary Objective ..........................................................................................................................................19 |
| 5.1.2                                                                                                                                                                  | Secondary Objectives ...................................................................................................................................19     |
| 5.1.3                                                                                                                                                                  | Exploratory Objective ..............................................................................................................................19         |
| 5.2                                                                                                                                                                    | Phase 2 Endpoints                                                                                                                                              |
| 5.3                                                                                                                                                                    | Phase 2 Objectives .                                                                                                                                           |
| 5.3.1                                                                                                                                                                  | Secondary Objective                                                                                                                                            |
| 5.3.2                                                                                                                                                                  | Exploratory Objectives                                                                                                                                         |
| 6 Patient Selection                                                                                                                                                    |                                                                                                                                                                |
| Inclusion Criteria .                                                                                                                                                   |                                                                                                                                                                |
| 6.1                                                                                                                                                                    | Conditions for Patient Ineligibility (Exclusion Criteria)                                                                                                      |
| 6.2                                                                                                                                                                    |                                                                                                                                                                |
| 7 Pretreatment Evaluations/Management                                                                                                                                  |                                                                                                                                                                |
| Informed Consent .                                                                                                                                                     |                                                                                                                                                                |
| 7.1                                                                                                                                                                    |                                                                                                                                                                |
| 7.2                                                                                                                                                                    | Screening Examination                                                                                                                                          |
| 8 Registration Procedures and Administrative Considerations                                                                                                            |                                                                                                                                                                |
| 8.1                                                                                                                                                                    | Enrollment Procedure .                                                                                                                                         |  
| Version 6.0, 30 Apr 2019                                                                                                                                       |                                                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| 8.2                                                                                                                                                            | Regulatory and Ethical Compliance                                                                                                                        |
| 8.3                                                                                                                                                            | Institutional Review Board and Protocol Review                                                                                                           |
| 8.4                                                                                                                                                            | Privacy, Confidentiality, and Data Storage .                                                                                                             |
| 8.5                                                                                                                                                            | Protocol Amendments                                                                                                                                      |
| 8.6                                                                                                                                                            | Conflict of Interest .                                                                                                                                   |
| 9 Radiation Therapy                                                                                                                                            |                                                                                                                                                          |
| 9.1                                                                                                                                                            | Dose Specification For Clinically Measurable Disease                                                                                                     |
| 9.2                                                                                                                                                            | Technical Factors                                                                                                                                        |
| 9.2.1                                                                                                                                                          | Treatment Planning/Delivery.                                                                                                                             |
| Image Guidance for IGRT                                                                                                                                        |                                                                                                                                                          |
| 9.2.2                                                                                                                                                          |                                                                                                                                                          |
| Localization, Simulation, and Immobilization .                                                                                                                 |                                                                                                                                                          |
| 9.3                                                                                                                                                            |                                                                                                                                                          |
| 9.4                                                                                                                                                            | Treatment Planning/Target Volumes                                                                                                                        |
| 9.4.1                                                                                                                                                          | Definition of Target Volumes for Unresected Patients (Who Receive Definitive                                                                             |
| Chemoradiation)                                                                                                                                                |                                                                                                                                                          |
| Definition of Target Volumes for Post-Operative Patients .............................................................30                                       |                                                                                                                                                          |
| 9.4.2                                                                                                                                                          |                                                                                                                                                          |
| 9.4.3                                                                                                                                                          | Definition of Normal Tissues/Organs at Risk (OAR) .....................................................................31                                |
| 9.4.4                                                                                                                                                          | IMRT Dose Constraints to Normal Structures ...........................................................................................32                 |
| Critical Structures                                                                                                                                            |                                                                                                                                                          |
| 9.5                                                                                                                                                            | Documentation Requirements for IMRT Approach .......................................................................................34                   |
| 9.6                                                                                                                                                            |                                                                                                                                                          |
| 9.7                                                                                                                                                            | RT Quality Assurance Reviews .........................................................................................................................35 |
| 9.7.1                                                                                                                                                          | Radiation Therapy / Adverse Events ..................................................................................................35                  |
| 10 Study Drug (Cisplatin)                                                                                                                                      |                                                                                                                                                          |
| 10.1 Description                                                                                                                                               |                                                                                                                                                          |
| 10.2 Formulation .                                                                                                                                             |                                                                                                                                                          |
| 10.3 Storage and Stability .                                                                                                                                   |                                                                                                                                                          |
| 10.4 Administration                                                                                                                                            |                                                                                                                                                          |
| 10.5 Dose Modifications  .                                                                                                                                     |                                                                                                                                                          |
| 10.5.1                                                                                                                                                         | Suggested dose modifications ........................................................................................................37                  |
| 10.5.2                                                                                                                                                         | Hematologic Toxicity ................................................................................................................................38  |
| 10.5.3                                                                                                                                                         | N Non-hematologic Toxicity                                                                                                                               |
| 10.6 Adverse Events                                                                                                                                            |                                                                                                                                                          |
| Risks of Phlebotomy .............................................................................................................................40            |                                                                                                                                                          |
| 10.6.1                                                                                                                                                         |                                                                                                                                                          |
| 10.7 Supply.................................................................................................................................................40 |                                                                                                                                                          |
| 1 STUDY DRUG (BMX-001) ...................................................................................................................................41   |                                                                                                                                                          |
| 1.1   Names, Classification, and Mechanism of Action ......................................................................................41                  |                                                                                                                                                          |  
| Version 6.0, 30 Apr 2019                                                                                                                                           |                                                                                                                                                         |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.2 Potential Benefits...................................................................................................................................41        |                                                                                                                                                         |
| 1.3 Packaging and Labeling ............................................................................................................................41          |                                                                                                                                                         |
| 11.3.1                                                                                                                                                             | Drug Product Formulation and Manufacture ...................................................................................41                          |
| 11.3.2                                                                                                                                                             | L Labels for BMX-001 for Injection, 10 mg/mL ......................................................................................42                   |
| 1.3.3                                                                                                                                                              | Syringe and Label for Administration of BMX-001 for Injection, 10 mg/mL ........................42                                                      |
| 1.3.4                                                                                                                                                              | Multi-Dose Kits .....................................................................................................................................42 |
| 1.4 Supply, Receipt, and Storage ........................................................................................................................43        |                                                                                                                                                         |
| 1.4.1                                                                                                                                                              | Compliance and Accountability                                                                                                                           |
| 11.4.2                                                                                                                                                             | Disposal and Destruction ..................................................................................................................43           |
| Dispensing and Preparation                                                                                                                                         |                                                                                                                                                         |
| 1.4.3                                                                                                                                                              |                                                                                                                                                         |
| 1.5 Phase 1 Administration by Dose Escalation at levels below established MTD....................................43                                                |                                                                                                                                                         |
| 1.6 Phase 2 Expanded ...........................................................................................................................................44 |                                                                                                                                                         |
| 1.7 Compliance and Accountability .............................................................................................................45                  |                                                                                                                                                         |
| 1.8 Concomitant Medications ...................................................................................................................45                  |                                                                                                                                                         |
| 1.9 Dose Modifications ...............................................................................................................................45           |                                                                                                                                                         |
| 1.10Management Guidelines for Potential BMX-001-induced Toxicities ...................................................46                                           |                                                                                                                                                         |
| 1.10.1                                                                                                                                                             | 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                                                                                                             |
| 11.11Dose-Limiting Toxicity (DLT) ................................................................................................................48               |                                                                                                                                                         |
| 1.11.1                                                                                                                                                             | N Non-hematologic                                                                                                                                       |
| Hematologic .............................................................................................................................48                        |                                                                                                                                                         |
| 11.11.2                                                                                                                                                            |                                                                                                                                                         |
| 1.11.3                                                                                                                                                             | O OTHER CONSIDERATIONS                                                                                                                                  |
| 1.12Adverse Events                                                                                                                                                 |                                                                                                                                                         |
| 1.13Risk Classification                                                                                                                                            |                                                                                                                                                         |
| 12 Other Therapy                                                                                                                                                   |                                                                                                                                                         |
| 12.1 Permitted Supportive Therapy                                                                                                                                  |                                                                                                                                                         |
| 12.2 Prohibited Therapies                                                                                                                                          |                                                                                                                                                         |
| 13 Screening and On-Study Tests and Procedures .                                                                                                                   |                                                                                                                                                         |
| 13.1 Evaluations During Treatment                                                                                                                                  |                                                                                                                                                         |
| 13.1.1                                                                                                                                                             | T Treatment Period .                                                                                                                                    |
| Physical Exam                                                                                                                                                      |                                                                                                                                                         |
| 13.1.2                                                                                                                                                             |                                                                                                                                                         |
| 13.1.3                                                                                                                                                             | Blood Pressure .                                                                                                                                        |
| EG .                                                                                                                                                               |                                                                                                                                                         |
| 13.1.4                                                                                                                                                             |                                                                                                                                                         |  
| Protocol #: BMX-HN-001                                                                                                                                             |                                                                                                                                                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Version 6.0, 30 Apr 2019                                                                                                                                           |                                                                                                                                                             |
| 13.1.5                                                                                                                                                             | Mucositis                                                                                                                                                   |
| 13.1.6                                                                                                                                                             | Xerostomia                                                                                                                                                  |
| 13.2   Re-treatment Criteria .                                                                                                                                     |                                                                                                                                                             |
| 13.3   Follow-up Period                                                                                                                                            |                                                                                                                                                             |
| 13.4   Early Withdrawal of Subject(s)                                                                                                                              |                                                                                                                                                             |
| 13.4.1                                                                                                                                                             | Criteria for Early Withdrawal ...........................................................................................................................56 |
| 13.4.2                                                                                                                                                             | Follow-up Requirements for Early Withdrawal                                                                                                                 |
| 13.5 End of Treatment                                                                                                                                              |                                                                                                                                                             |
| 13.6 End of Study                                                                                                                                                  |                                                                                                                                                             |
| Early Study Termination .............................................................................................................................57            |                                                                                                                                                             |
| 13.6.1                                                                                                                                                             |                                                                                                                                                             |
| 13.7   Outcomes Criteria .                                                                                                                                         |                                                                                                                                                             |
| Time-to-Event Variables .............................................................................................................................57            |                                                                                                                                                             |
| 13.7.1                                                                                                                                                             |                                                                                                                                                             |
| 13.7.2                                                                                                                                                             | Radiographic Response                                                                                                                                       |
| 13.8   Quality of Life and Functional Assessments: HRQoL                                                                                                           |                                                                                                                                                             |
| 14 Safety Monitoring and Reporting .                                                                                                                               |                                                                                                                                                             |
| 14.1 Adverse Events                                                                                                                                                |                                                                                                                                                             |
| 14.1.1                                                                                                                                                             | Reporting of AEs                                                                                                                                            |
| 14.2 Serious Adverse Events                                                                                                                                        |                                                                                                                                                             |
| Reporting of SAEs ..............................................................................................................................................60 |                                                                                                                                                             |
| 14.2.1                                                                                                                                                             |                                                                                                                                                             |
| 14.3 External Data and Safety Monitoring Board (DSMB) ...............................................................................61                            |                                                                                                                                                             |
| 14.4 Monitoring                                                                                                                                                    |                                                                                                                                                             |
| 14.5 Audits                                                                                                                                                        |                                                                                                                                                             |
| 15 Data Management and Processing ..................................................................................................................63             |                                                                                                                                                             |
| 15.1 Study Documentation                                                                                                                                           |                                                                                                                                                             |
| 15.2   Case Report Forms (CRFs).................................................................................................................................63 |                                                                                                                                                             |
| 15.3   Data Management Procedures and Data Verification .............................................................................63                            |                                                                                                                                                             |
| 15.4 Coding                                                                                                                                                        |                                                                                                                                                             |
| 15.5 Study Closure .                                                                                                                                               |                                                                                                                                                             |
| 15.6   Records Retention                                                                                                                                           |                                                                                                                                                             |
| 16 Statistical Methods and Data Analysis ...............................................................................................................65         |                                                                                                                                                             |
| Analysis Sets                                                                                                                                                      |                                                                                                                                                             |
| 16.1.1                                                                                                                                                             |                                                                                                                                                             |
| 16.1.2                                                                                                                                                             | Patient Demographics and Other Baseline Characteristics .........................................................65                                         |
| T Treatments                                                                                                                                                       |                                                                                                                                                             |
| 16.1.3                                                                                                                                                             |                                                                                                                                                             |
| 16.1.4                                                                                                                                                             | Phase 1 Dose Escalation .....................................................................................................................65             |
| Objectives ..................................................................................................................................................65    |                                                                                                                                                             |
| 16.1.5                                                                                                                                                             |                                                                                                                                                             |  
| Protocol #: BMX-HN-001                                                                                                                                  |                                                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| Version 6.0, 30 Apr 2019                                                                                                                                |                                                                                                                                                  |
| 16.2   Phase 2                                                                                                                                          |                                                                                                                                                  |
| 16.2.1                                                                                                                                                  | Primary Endpoint                                                                                                                                 |
| 16.2.2                                                                                                                                                  | Objectives/Endpoint and Data Analyses                                                                                                            |
| 16.2.3                                                                                                                                                  | Interim Analysis for Phase 2                                                                                                                     |
| 16.2.4                                                                                                                                                  | Sample Size Calculation for Phase 2 ..........................................................................................................69 |
| 17 References                                                                                                                                           |                                                                                                                                                  |
| Appendix A: Functional Assessment of Cancer Therapy - Head and Neck (Version 4) ........................................74                              |                                                                                                                                                  |
| Appendix B: Oral Mucositis Weekly Questionnaire - HN ................................................................................................7  |                                                                                                                                                  |
| Appendix C: Xerostomia-Related Quality of Life Scale .............................................................................................79    |                                                                                                                                                  |
| Appendix D: Dermatology Life Quality Index ..........................................................................................................80 |                                                                                                                                                  |
| Appendix E: PRO-CTCAE-HN                                                                                                                                |                                                                                                                                                  |
signature page sponsor signature page
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                                    |  
| 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                                                               |  
3
schema of clinical trial
2 list of abbreviations

A Phase 1/2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-001 in Locally Advanced Head and Neck Cancer  
  
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.
schema of clinical trial
4 introduction 4.1 head and

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.
schema of clinical trial
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 complications 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 complications. 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.
schema of clinical trial
4.2 bmx-001

It is well established that induction of oxidative stress after radiation therapy (RT) and chemotherapy 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 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 [1012]. 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 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 BMX001 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.
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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 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.
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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 3040 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.
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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 studydrug-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 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.
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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.
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4.4.2 rationale for selection of

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.
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4.5 quality of life and

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 multidimensional 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 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 5point 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 OMWQHN and the PSS-HN were not as strongly correlated (η range = −0.09 to −0.37), suggesting that 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 symptomfocused 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, inflammation, 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].
schema of clinical trial
5 objectives 5.1 phase 1

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.
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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, 5059 Gy, and 60-70 Gy, the duration of xerostomia, and evaluation of xerostomiarelated 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.
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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.
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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.  
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.
schema of clinical trial
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.
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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 nontherapeutic 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.  
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.
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6.2 conditions for patient ineligibility

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. 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.
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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 betaHCG 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

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.
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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.
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8.3 institutional review board and

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.
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8.4 privacy confidentiality and data

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 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.
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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).  
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.
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9.1 dose specification for clinically

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 1.431.5 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 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 oncedaily 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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9.2.2 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);
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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.
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9.4 treatment planning/target volumes 9.4.1

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

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

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. 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.
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9.4.4 imrt dose constraints to

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. 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.  
| 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                                                                          |  
9.5 **Critical Structures**
The following table outlines the various normal and critical structures. Institutional standards may be used instead.  
| 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)                                                                                |
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9.6 documentation requirements for imrt

- 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                                                                                                            | 70 Gy                  | None               | None    |
| the PTV) 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 | < 66.5 but > 63 Gy | ≤ 63 Gy |
| prescribed dose)                                                                                                                            |                        |                    |         |
| Maximum dose ("hot spot" >                                                                                                                  | ≤ 77 Gy                | > 77 but ≤ 82 Gy   | > 82 Gy |
| 1cc) within PTV1 Maximum dose ("hot spot" >                                                                                                 | < 74 Gy                | 74-77 Gy           | > 77 Gy |
| 1cc outside the PTVs)                                                                                                                       |                        |                    |         |  
| Per Protocol                              | Variation Acceptable                         | Deviation                                                         |                                                                   |
|-------------------------------------------|----------------------------------------------|-------------------------------------------------------------------|-------------------------------------------------------------------|
| Unacceptable                              |                                              |                                                                   |                                                                   |
| Total dose to PTV2 (to 95% of             | 56 Gy                                        | ≥ 45 but < 56 Gy                                                  | < 45 Gy                                                           |
| the PTV) Total dose to PTV3 (to 95% of    | 50-52.5 Gy                                   | ≥ 40 but < 50 Gy                                                  | < 40 Gy                                                           |
| the PTV) Total RT dose to spinal cord PRV | ≤ 50 Gy                                      | ≥ 50 but ≤ 52 Gy                                                  | > 52 Gy                                                           |
| (0.03 cc) 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                   | 0-2                                          | 2-4                                                               | > 4                                                               |
| Treatment Interruptions                   |                                              |                                                                   |                                                                   |  
9.7 **RT Quality Assurance Reviews**
RT Quality Assurance Reviews will be done with participating radiation oncology investigators with regularly scheduled discussions.
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9.7.1 radiation therapy / adverse

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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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
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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.
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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.  
| 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)   |  
| 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                                                   | Decrease by 1 dose level                                                                                   |
| Grade 3 Nausea/vomiting ≤ Grade 2 with maximal medical    | Maintain dose level                                                                                        |
| management Intolerable grade 2 with maximal               | Decrease by 1 dose level                                                                                   |
| medical management ≥ Grade 3 with maximal medical         | Hold drug until ≤ grade 2 then resume                                                                      |
| management                                                | at one lower dose level                                                                                    |
| Mucositis in RT field                                     | Hold drug until ≤ grade 3                                                                                  |  
| 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.  
- 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.
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summary of possible side effects

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
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rare and serious

In 100 people receiving cisplatin, 3 or fewer may have:
- Cancer of bone marrow later in life caused by chemotherapy
- Seizure
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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

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 antitumor functions. A series of metalloporphyrins have undergone preclinical evaluation, and BMX001 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.
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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.
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11.3 packaging and labeling 11.3.1

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). 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 inprocess 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.
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11.3.2 labels for bmx-001 for

An exemplary label for the BMX-001 for Injection, 10 mg/mL is reproduced in Figure 3.
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11.3.3 syringe and label for

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.
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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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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 longterm stability studies currently underway at AMRI (Glasgow) Ltd. At the present time, no significant drug degradation has been observed under storage conditions.
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11.4.1 compliance and accountability

Drug accountability records will be maintained for all clinical trial supplies.
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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.
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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.
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11.5 phase 1 administration by

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. 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.  
| 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         |
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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 enrollment. 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.                                                                                |  
| NCI CTCAE toxicity                                                                           | BMX-001 dose                                                                                                                                                                                                  |
|----------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Other ≥ grade 3 attributable to                                                              | Discontinue BMX-001.                                                                                                                                                                                          |
| 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;                                                              | Discontinue BMX-001.                                                                                                                                                                                          |
| >60 ms change from baseline)                                                                 |                                                                                                                                                                                                               |  
Regardless of the reason for holding study drug treatment, the maximum allowable length of treatment interruption is 3 weeks.
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11.10 management guidelines for potential

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.
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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.
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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 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.
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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.
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11.10.4 prolongation of qtc interval

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.  
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 QTprolonging 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.
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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 medications; b) occurs during and/or following the first dose of BMX-001; and c) meets any of the following criteria:
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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 drugrelated toxicity to re-treatment criteria or pre-treatment baseline.
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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);
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
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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 (BMXHGG 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 doserelated 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. 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.
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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, antiemetics, 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.
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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 - Use of drugs known to lengthen QT intervals should be avoided or minimized.  
| On-Study Tests and Procedures                                      |                                    |         |    |    |    |    |    |          |    |    |          |
|--------------------------------------------------------------------|------------------------------------|---------|----|----|----|----|----|----------|----|----|----------|
| Evaluation                                                         | Screeninga                         | Baselinea         | Wk | Wk | Wk | Wk | Wk | Wk       | Wk | Wk | Wk 9 and |
| 1                                                                  | 2                                  | 3       | 4  | 5  | 6  | 7  | 8  | Forwardb |    |    |          |
| Day  -4 to 0                                                       |                                    |         |    |    |    |    |    |          |    |    |          |
| Informed consent                                                   | X                                  |         |    |    |    |    |    |          |    |    |          |
| History and                                                        | X                                  | X       | X  | X  | X  | X  | X  | X        | X  | X  | X        |
| physical examb 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                                                     | X                                  | X       | X  | X  | X  | X  | X  | X        | X  | X  |          |
| and heart ratec CBC with                                           | X                                  | X       | X  | X  | X  | X  | X  | X        | X  | X  |          |
| differentialb CMPb                                                 | X                                  | X       | X  | X  | X  | X  | X  | X        | X  | X  |          |
| PT/aPTT                                                            | X                                  |         |    |    |    |    |    |          |    |    |          |
| Serum beta-HCG                                                     | Xj                                 |         |    |    |    |    |    |          |    |    |          |
| ECGd                                                               | X                                  | X       | X  | X  |    |    |    |          |    |    |          |
| Mucositisb                                                         | X                                  | X       | X  | X  | X  | X  | X  | X        | X  | X  | X        |
| (clinical score) 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                                                           | X                                  | Ongoing | X  |    |    |    |    |          |    |    |          |
| Assessment 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 |         |    |    |    |    |    |          |    |    |          |
schema of clinical trial
13 screening and on-study tests

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 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.
schema of clinical trial
13.1 evaluations during treatment 13.1.1

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.
schema of clinical trial
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.
schema of clinical trial
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.
schema of clinical trial
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.
schema of clinical trial
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.
schema of clinical trial
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 BMX001 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 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.
schema of clinical trial
13.4 early withdrawal of subject(s)

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