Clinical trial NCT03307629
Conditions: Cancer
Sponsor: Noxopharm Limited
Start date: 2017-11-01; Completion date: 2020-09-15
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is intended as a Proof of Concept and dose confirmation study. The primary objective of this study is to observe safety and tolerability of idronoxil (NOX66) in combination with radiotherapy (at palliative doses) in patients with metastatic castrate-resistant prostate cancer (CRPC) and to confirm dose in order to progress to Phase 2/3.

Detailed description:
This study will investigate three escalating doses of NOX66 in combination with palliative dose of radiation therapy to establish safety profile and / or obtain efficacy signals and to determine the optimal dose for future radiation therapy combination studies.

The key hypotheses to be tested in this study are:

1. That NOX66 can be safely added to palliative dose radiation therapy.
2. That NOX66 may sensitise tumours to palliative doses of radiation therapy
3. That NOX66 in combination with radiation therapy may trigger or augment an abscopal effect

Participants will have a minimum of 1 symptomatic lesion amenable to radiation therapy.

Radiation therapy will be delivered at a 20Gy dosage over 5 fractions. NOX66 will be taken on 13 consecutive days starting 1 day prior to radiotherapy.

The response of irradiated and non-irradiated target tumour lesions will be measured by CT/MRI scan and RECIST1.1 criteria at three time points post treatment. Pain response will be evaluated using the Brief Pain Inventory-Short Form (BPI-SF) instrument at five time points post treatment.

Patients will be suitable for the study as they become indicated for palliative radiation therapy for management of their cancer.

This study will enrol up to 24 patients in 3 NOX66 dose level cohorts of 4 patients (n=12) and an expansion cohort of 12 patients. Dose escalation decisions will be based on patients who experience adverse events directly related to NOX66 treatment.

Following the review of accumulated safety data, disease status and treatment efficacy signals at WEEK 6 for the first 12 patients, the Study Steering Committee will determine the dose at which to continue treatment for the expansion patient Cohort 4 in the study. A further 12 patients will be recruited at this dose level.

Arms: arm 1: NOX66 administered on Days 1-16 and radiation treatment given on Day 2 to 9 of 2-week cycle.

NOX66 treatment given to 3 cohorts of 4 patients as 1 of 3 doses, 400mg, 800mg and 1200 mg.

Radiation treatment of 20Gy given over 5 daily fractions to selected target lesion/s for all cohorts. arm 2: NOX66 administered on Days 1-16 and radiation treatment given on Day 2 to 9 of 2-week cycle.

NOX66 dose will be either one of 3 doses 400mg, 800mg and 1200 mg based on interim analyses of safety data and tumour response at WEEK 6 of 3 dose cohorts of 12 total patients. The Safety Steering Committee will inform on dose for cohort expansion.

Radiation treatment of 20Gy given over 5 daily fractions to selected target lesion/s for all cohorts.
Interventions: intervention 1: NOX66 intervention 2: Irradiation Therapy
Intervention descriptions: intervention 1: NOX66 delivered as rectal suppository. intervention 2: Radiation per selected tumour lesion.

Protocol documents:
Prot_SAP_000.pdf: 
NOXOPHARM LIMITED 
 
CONFIDENTIAL 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
NOX66 and Palliative Radiotherapy in Patients with Late-Stage Prostate 
Cancer – a Phase 1b Proof of Concept and Dose confirmation study. 
 
Protocol Number: 
NOX66-002A 
 
Development Phase: 1b 
 
Product: 
 
NOX66 (Idronoxil Suppository Formulation) 
 
Sponsor: 
Noxopharm Limited 
Suite 3, Level 4 
828 Pacific Highway, Gordon, NSW, Australia 
Telephone:  
+61 2 9144 2223 
 
 
 
Version: 
 
5.1 
 
Date:  
 
 11 July 2019  
 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you for the exclusive use as an 
investigator or consultant for review by you, you staff, and the applicable HREC, and is patient to recall 
at any time. Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorisation from Noxopharm Ltd. These 
restrictions on disclosure apply to all future oral or written information supplied to you that is 
designated as ‘Privileged’ or ‘Confidential’. 
 


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SIGNATURES 
SPONSOR 
 
This document has been approved in accordance to Noxopharm Limited’s current policies 
and procedures 
 
 
 
Dr.Greg van Wyk  
Chief Executive Officer & Chief Medical Officer 
Noxopharm Limited 
 
Date 
 
 
INVESTIGATOR 
I confirm that I have read and understood the protocol and I agree to meet all the obligations 
and restrictions outlined therein. All information regarding this protocol and the 
investigational product(s) will be treated as strictly confidential. I agree to conduct the study 
in all respects in accordance with the study protocol and the ethical principle of the current 
amendment of the declaration of Helsinki and with ICH GCP.  
 
 
___________________________ 
 
_____________________________ 
Signature of Principal Investigator  
Date 
 
 
 
 
___________________________ 
 
_______________________________________ 
Printed Name of Principal Investigator 
Institution Name 
 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Company Sponsor 
NOXOPHARM LIMITED 
Title of Study 
NOX66 and Palliative Radiotherapy in Patients with Late-Stage Prostate Cancer 
– a Phase 1b Proof of Concept and dose confirmatory study. 
Study Number 
NOX66-002A 
Development phase 
Phase Ib 
Name of Active Ingredient  
Idronoxil 
Description of 
Investigational product 
NOX66 is idronoxil in a hydrogenated lipophilic base formulated as a 
suppository, designed to protect idronoxil from Phase 2 metabolism. 
Mode of Administration 
and dosage 
NOX66 will be self-administered as a rectal suppository. Patients will be 
instructed in the procedure of suppository administration  
Dosage is 1, 2 or 3 suppositories (idronoxil dosage 400mg, 800mg or 1200mg) 
for 13 (+3) consecutive days.  
Number of subjects 
planned 
Up to 24 patients in 3 idronoxil dose level cohorts of 4 patients (n=12) and an 
expansion cohort of 12 patients. 
Indication / Patient 
Population 
Metastatic castrate-resistant prostate cancer with no remaining standard 
treatment options. Patients must have at least one metastatic lesion which is 
amenable to RT. 
Study period and duration 
of treatment 
The study will comprise two parts:  
1. Treatment and follow up (24 weeks) comprising: 
• NOX66 (Day 1-16) 
• Palliative Dose Radiation therapy (Day 2-9) 
• 6-week follow up 
• 12-week follow up 
• 24-week follow up 
2. Long term follow-up: 
• Ongoing follow up and monitoring of patient to assess long term 
effects of NOX66 administration and survival including scheduled 
follow up at 9 ,12, 15, 18, 21 & 24 months from treatment 
commencement date.  
Primary study objective 
• To determine the tolerability and toxicity of NOX66 administered in 
conjunction with palliative radiation therapy 
Secondary study objectives 
• To observe any clinical response to treatment of NOX66 in combination 
with palliative radiation therapy 
• To observe the effects of NOX66 use on long term (24 months) outcomes 
for patients 


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• To document Progression Free Survival (PFS) and Overall Survival (OS) of 
patients 
• Exploratory:  to measure levels of idronoxil  
Methodology 
Patients will have a minimum of one (1) lesion which is amenable to radiation 
therapy and be treated in combination with idronoxil (NOX66).  
The Study will involve 13-16 days of treatment with NOX66 and radiation 
therapy as follows: 
• Baseline: Tumour assessment scan using CT/MRI, screening laboratory 
assessments (including PSA levels), and pain assessment (Brief pain 
Inventory-Short Form) 
• Day 1-16: NOX66 will be administered rectally (one, two or three 
suppositories daily, depending on cohort allocation) 
• Day 2-9: Lesions selected for irradiation will receive palliative dose (20Gy) 
radiation therapy in 5 fractionated doses over 7 days. 
• Week 6: Initial follow up scan using CT/MRI, follow up laboratory 
assessments (including PSA levels), and pain assessment 
• Week 12: Second follow up scan using CT/MRI, follow up laboratory 
assessments (including PSA levels), and pain assessment 
• Week 24: third follow up scan using CT/MRI, follow up laboratory 
assessments (including PSA levels), and pain assessment 
• Month 9 (3 months after Week 24): Performance Status (ECOG), scan 
using CT/MRI/US, PSA measure and pain assessment. 
• Month 12: Performance Status ECOG), scan using CT/MRI, PSA measure 
and pain assessment. 
• Month 15, 18, 21 & 24 (every 3 months after Month 12 follow up visit for 
another 12 months): Scan using CT/MRI/US & PSA measure. 
Patients will continue to be followed up after 24 months at the discretion of 
the investigator. 
The study steering committee (SSC) will review emerging safety data and 
determine the dose cohort escalation following end of treatment cycle of final 
patient in a cohort. Following interim analyses of safety data and tumour 
response at WEEK 6 of 3 dose cohorts of 12 total patients, the SSC will inform 
on dose for cohort expansion of additional 12 patients. 
Baseline CT/MRI scans shall be assessed and any lesions which can be 
measured in accordance with RECIST criteria will be noted as “target lesions”. 
Target measurable lesions may either be at the site of irradiation or non-
irradiated. Patients with identified measurable target lesions will be assessed 
for objective response using RECISTv1.1 criteria. All patients will have 
radiological scans, PSA, ECOG and pain scores assessed for clinical response by 
a Radiation Oncology Expert Committee. 
Criteria for Evaluation 
Safety: assessed through the analysis of routine clinical and laboratory 
assessments 
of 
haematology 
and 
chemistry 
parameters, 
physical 


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examinations and vital signs. Adverse event monitoring will be performed and 
assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.03 (CTCAE) scoring system. 
Efficacy: Overall response will be assessed by a Radiation Oncology Expert 
Committee based on change from baseline of tumours on imaging data by 
RECISTv1.1 criteria for measurable lesions, total pain score, PSA and ECOG 
score. 
Biomarkers: Serum levels of PSA will be measured at baseline and four-time 
points (end of Treatment Cycle (Day 16), at Week 6 ,12 and 24 post therapy. 
Plasma levels of idronoxil will be measured at baseline and two post therapy 
time points, end of Treatment Cycle (Day 16) and at Week 6. 
 
Statistical methods 
No statistical analysis of results will be conducted due to the size of the cohort. 
Primary endpoint will be reported as the number of patients experiencing 
toxicity >2 and dose limiting toxicities (DLT) with description of the toxicity.  
Secondary endpoints will be reported as the response (measured and 
observed) to treatment of each patient over the 24-week initial period. Data 
will be presented in table form, with adverse events and outcomes listed per 
patient. 
Overall and progression-free survival, PSA and pain scores collected during the 
extended follow-up period will be summarized in the same manner as for the 
immediate post-treatment follow-up period. 
A detailed Statistical Analysis Plan will be developed and approved prior to 
data lock.  
Inclusion criteria 
1. Provision of informed consent.  
2. ≥ 18 years of age. 
3. Histologically confirmed prostate cancer and/or PSA of >100 ng/mL at 
original diagnosis. 
4. Metastatic disease evidenced by either CT/MRI imaging or bone scan. 
5. Objective evidence of disease progression as defined by either: 
i. 
Radiographic progression of in nodal or visceral metastases and 
bone disease progression with 2 or more new lesions  
ii. 
Rising PSA value ≥2ng/ml in at least 3 measurements, at least 1 week 
apart, with castrate levels of serum testosterone. 
6. Eligible to receive palliative radiation therapy to at least one symptomatic 
lesion for management of disease.  
7. ECOG Performance status 0-2. 
8. A minimum life expectancy of 24 weeks. 
9. Adequate bone marrow, hepatic and renal function as evidenced by:  
• Absolute neutrophil count (ANC) > 1.5 x 109/L  
• Platelet count > 100 x 109/L  
• Hemoglobin > 9.0 g/dL  
• Serum bilirubin < 1.5 x ULN  


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• AST/ALT (SGOT/SGPT) < 2.5 x ULN for the reference laboratory or   
< 5 x ULN in the presence of liver metastases  
• Serum creatinine < 1.5 x ULN  
10. Ongoing androgen deprivation therapy with luteinizing hormone-
releasing hormone (LHRH) agonist or antagonist. 
11. At least 4 weeks must have elapsed prior to commencement of NOX66 
treatment since prior chemotherapy, investigational drug or biologic 
therapy and any toxicity associated with these treatments has recovered 
to ≤ NCI-CTCAE (version 4.03) Grade 1. 
12. At least 21 days must have elapsed following major surgery and any 
surgical incision should be completely healed. 
Exclusion criteria 
1. Tumour involvement of the central nervous system.  
2. Uncontrolled infection or systemic disease.  
3. Clinically significant cardiac disease not well controlled with medication 
(e.g. congestive heart failure, symptomatic coronary artery disease, 
angina, and cardiac arrhythmias) or myocardial infarction within the last 
12 months.  
• 
Patients with a QTc > 470 msec on screening ECG 
4. Concurrent systemic chemotherapy or biological therapy. 
5. Any situation where the use of suppository therapy is contra-indicated or 
impractical (e.g. chronic diarrhoea, colostomy, ulcerative colitis). 
6. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, 
previously treated or both).  
7. Any subject whose testosterone is not suppressed i.e. is > 0.5nmols/L. 
8. Any other reason which, in the opinion of the investigator, will preclude 
suitable participation in the study. 
 
 
 


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TABLE OF CONTENTS 
Protocol Synopsis ....................................................................................................................... 3 
1 
LIST OF TABLES AND FIGURES .......................................................................................... 11 
2 
LIST OF ABBREVIATIONS .................................................................................................. 12 
3 
Roles and Responsibilities ................................................................................................ 14 
3.1 
Sponsor ...................................................................................................................... 14 
3.2 
Contract resesarch organisation ............................................................................... 14 
3.3 
Investigator and Sites ................................................................................................ 14 
3.4 
Medical Oversight ..................................................................................................... 14 
4 
Introduction ..................................................................................................................... 15 
4.1 
Multi-drug resistance, chemo- and radio-sensitisation and idronoxil ...................... 15 
4.2 
Idronoxil – A selective inhibitor of PI3K/Akt ............................................................. 16 
4.3 
Idronoxil – Summary of mechanism of action .......................................................... 17 
4.4 
Idronoxil – intravenous and oral dosage formulation .............................................. 18 
4.5 
Idronoxil – NOX66 dosage formulation ..................................................................... 18 
4.6 
NOX66 – Current drug development program ......................................................... 19 
5 
Study Rationale ................................................................................................................ 20 
5.1 
Rationale for Combination with Radiation therapy .................................................. 20 
5.1.1 
Radio-sensitisation ............................................................................................. 20 
5.1.2 
Abscopal Response ............................................................................................ 20 
5.2 
Rationale for Dose of NOX66 .................................................................................... 21 
5.3 
Potential Risks ........................................................................................................... 21 
5.4 
potential benefits ...................................................................................................... 22 
6 
STUDY OBJECTIVES AND HYPOTHESES ............................................................................ 23 
6.1 
Primary Objective ...................................................................................................... 23 
6.2 
Secondary Objectives ................................................................................................ 23 
7 
STUDY DESIGN ................................................................................................................. 24 
8 
STUDY PARTICIPANTS ...................................................................................................... 24 
8.1 
Study Population ....................................................................................................... 24 
8.2 
Inclusion criteria ........................................................................................................ 25 


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8.3 
Exclusion Criteria ....................................................................................................... 25 
8.4 
Screen Failure and study withdrawal ........................................................................ 26 
8.5 
Patient Replacement ................................................................................................. 27 
9 
STUDY MATERIALS ........................................................................................................... 27 
9.1 
Investigational Study Product ................................................................................... 27 
9.1.1 
Description and Formulation ............................................................................. 27 
9.1.2 
Presentation, Storage and Handling .................................................................. 27 
9.1.3 
Labelling ............................................................................................................. 28 
9.1.4 
Procurement and Distribution ........................................................................... 28 
9.2 
INVESTIGATIONAL PRODUCT ADMINISTRATION ...................................................... 28 
9.3 
RADIATION THERAPY ................................................................................................. 29 
9.4 
TREATMENT DOSE MODIFICATIONS AND TREATMENT CYCLE DELAY ...................... 30 
9.4.1 
NOX66 ................................................................................................................ 30 
9.4.2 
Radiation Therapy .............................................................................................. 30 
9.5 
ACCOUNTABILITY FOR CLINICAL SUPPLIES................................................................ 30 
9.6 
CONCOMITANT MEDICATIONS ................................................................................. 30 
10 STUDY PROCEDURES ........................................................................................................ 31 
10.1 
OUTCOME MEASURES ........................................................................................... 31 
10.2 
STUDY VISITS .......................................................................................................... 32 
10.2.1 Screening Visit (VS) ............................................................................................ 32 
10.2.2 Enrolment Visit (V1): .......................................................................................... 33 
10.2.3 Treatment Cycle (Days 1-16) - Visits 2 to 7 ........................................................ 33 
10.2.4 Six-Week Follow up (Day 43 ± 5) - Visit 8 .......................................................... 35 
10.2.5 Twelve-Week Follow up (Day 84 ± 7) - Visit 9 ................................................... 35 
10.2.6 Eighteen -Week administration BPI-SF (Day 125 ± 5) ........................................ 35 
10.2.7 Twenty-Four Weeks Follow up/ end of study (Day 168 +7) -VISIT 10 ............... 35 
10.2.8 Month 9 Long Term Follow up  -Visit 11 ............................................................ 36 
10.2.9 Month 12 Long Term Follow up -Visit 12........................................................... 36 
10.2.10 
Month 15 Long Term Follow up -Visit 13 ....................................................... 37 
10.2.11 
Month 18 Long Term Follow up -Visit 14 ....................................................... 37 
10.2.12 
Month 21 Long Term Follow up – Visit 15 ..................................................... 37 


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10.2.13 
Month 24 Long Term Follow up -Visit 16 ....................................................... 37 
10.2.14 
Cohort Allocation and Dose Escalation .......................................................... 38 
10.3 
POST STUDY Observation ...................................................................................... 39 
10.4 
Clinical Assessments .............................................................................................. 39 
10.4.1 Medical History and demography ..................................................................... 39 
10.4.2 Physical examination ......................................................................................... 40 
10.4.3 ECOG Performance assessment ......................................................................... 40 
10.4.4 Electrocardiography ........................................................................................... 40 
10.4.5 Brief Pain Inventory-Short Form ........................................................................ 40 
10.4.6 Safety Blood Sampling ....................................................................................... 41 
10.4.7 Biomarker Sampling ........................................................................................... 41 
10.4.8 Tumour Imaging ................................................................................................. 41 
10.4.9 Radiation Oncology Expert Committee ............................................................. 43 
11 DATA COLLECTION AND MANAGEMENT ......................................................................... 43 
11.1 
METHODS .............................................................................................................. 43 
11.1.1 Case report form ................................................................................................ 44 
11.1.2 Return and storage of forms .............................................................................. 44 
11.2 
DATA MANAGEMENT ............................................................................................ 44 
11.2.1 Data Coding ........................................................................................................ 44 
11.2.2 Data validation ................................................................................................... 44 
12 STATISTICAL SECTION....................................................................................................... 44 
12.1 
SAMPLE SIZE .......................................................................................................... 44 
12.2 
STATISTICAL METHODOLOGY ................................................................................ 45 
12.3 
PROCEDURES FOR HANDLING MISSING, UNUSED AND SPURIOUS DATA ............ 46 
13 MONITORING ................................................................................................................... 47 
13.1 
MONITORING OF CASE REPORT FORMS ............................................................... 47 
13.2 
SAFETY DATA MONITORING .................................................................................. 47 
13.3 
AUDITING ............................................................................................................... 47 
14 ADVERSE EVENTS REPORTING ......................................................................................... 48 
14.1 
DEFINITIONS .......................................................................................................... 48 
14.1.1 AE ....................................................................................................................... 48 


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14.1.2 SAE ..................................................................................................................... 48 
14.1.3 Guidelines for determining causality and severity ............................................ 49 
14.2 
RESPONSIBILITIES FOR REPORTING ....................................................................... 50 
14.2.1 SAE and Unresolved AE Follow-Up .................................................................... 51 
14.2.2 Investigator Reporting of AEs/SAEs/Deaths after Study Discontinuation ......... 51 
14.2.3 Sponsor SAE Reporting Requirements ............................................................... 52 
15 CONDUCT OF STUDY ........................................................................................................ 53 
15.1 
HUMAN RESEARCH ................................................................................................ 53 
15.2 
GOOD CLINICAL PRACTICE ..................................................................................... 53 
15.3 
ADHERENCE TO PROTOCOL ................................................................................... 53 
15.4 
PROTOCOL AMENDMENTS .................................................................................... 54 
16 PATIENT INFORMED CONSENT ........................................................................................ 55 
17 DISCLOSURE OF DATA ...................................................................................................... 55 
17.1 
CONFIDENTIAL INFORMATION .............................................................................. 55 
17.1.1 Study records and source documents ............................................................... 56 
17.1.2 Prior to study commencement .......................................................................... 56 
17.1.3 Document retention .......................................................................................... 57 
17.1.4 Access to source documents ............................................................................. 57 
17.1.5 Publication policy ............................................................................................... 57 
18 ADDITIONAL PATIENT CARE DURING POST-STUDY ......................................................... 58 
18.1 
EMERGENCY CONTACT .......................................................................................... 58 
18.1.1 Investigator ........................................................................................................ 58 
18.1.2 Sponsor .............................................................................................................. 58 
18.1.3 Liability and Insurance ....................................................................................... 58 
19 REFERENCES ..................................................................................................................... 59 
20 APPENICIES ....................................................................................................................... 62 
20.1 
Appenidix 1- ECOG Score* ..................................................................................... 62 
20.2 
Appendix 2- BPI-SF ................................................................................................. 63 
20.2 
Appendix 2- BPI-SF ................................................................................................. 63 
 
 
 


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1 LIST OF TABLES AND FIGURES 
Figure 1 Sequence of biochemical events following binding of idronoxil to ENOX2. ............. 17 
Table 1. Schedule of Assessments: TREATMENT CYCLE .......................................................... 34 
Figure 2: Dose Escalation and Dose Expansion Schema .......................................................... 39 
Table 2 Criteria for determining relationship between AE and idronoxil (NOX66) ................. 49 
Table 3. Adverse event outcome categories ........................................................................... 50 
 
 
 


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2 LIST OF ABBREVIATIONS 
 
Abbreviation/term 
Definition 
AE 
Adverse Event 
Akt 
Protein kinase B 
ALP 
Alkaline Phosphatase 
ALT/SGT 
Alanine Transaminase / Serum Glutamate pyruvate Transaminase 
AST/SGOT 
Aspartate aminotransferase/ Serum Glutamate Oxaloacetate Transaminas 
β-hCG 
Beta-human Chorionic Gonadotropin  
BPI-SF 
Breif Pain Inventory- Short Form 
0C 
Degrees Celsius 
CBC 
Complete blood count (otherwise known as FBC) 
c-FLIP 
Cellular FLICE [FADD-like IL-1b-converting enzyme]-inhibitory protein 
CFR 
Code of Federal Regulations 
CRF/eCRF 
Case report form/electronic Case report form 
CR 
Complete Response 
CRO 
Contract Research Organisation 
CSA 
Clinical Study Agreement 
CT 
Computerised Tomography 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiograph 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ENOX 
External Membrane NADH oxidase  
ENOX1 
ENOX Type 1 - Constitutive NADH oxidase  
ENOX2 
ENOX Type 2 - Tumour-associated NADH oxidase 
FDA 
Food and Drug Administration 
g 
Gram(s) 
Gy 
Gray 
HIV 
Human Immunodeficiency Virus 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH GCP 
International Conference on Harmonization Good Clinical Practice 
ICRU 
International Commission on Radiation Units 
IV 
Intravenous 
kg 
Kilogram 
LD 
Longest Diameter 
LHRH 
Luteinizing hormone-Releasing Hormone 
µ 
Micro 
µM 
Micromolar 


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MDR 
Multidrug Resistance 
mg 
Milligram(s) 
mL 
Milliliter(s) 
min 
Minute(s) 
msec 
Millisecond 
MCH 
Mean Corpuscular Haemoglobin  
MCV 
Mean Corpuscular Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro Ribose Nucleic Acid 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NAD(H) 
Nicotinamide Adenine Dinucleotide 
NCI CTC 
National Cancer Institute, Common Toxicity Criteria 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NK 
Natural Killer cells 
OS 
Overall Survival 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PI3K/Akt 
Phosphoinositide 3-kinase /protein Kinase B 
PFS 
Progression Free Survival 
PMSA 
Prostate Membrane Specific Antigen 
PSA 
Prostate Specific Antigen 
PR 
Partial Response 
PT 
Preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROEC 
Radiation Oncology Expert Committee 
RT 
Radiation therapy 
S1P 
Sphingosine-1-phosphate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SSC 
Study Steering Committee 
SOC 
System Organ Class 
TGA 
Therapeutic Goods Administration 
ULN 
Upper Limit of Normal 
US 
Ultrasound 
XIAP 
X-linked inhibitor of Apoptosis Protein 
 
 
 
 
 


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3 ROLES AND RESPONSIBILITIES 
3.1 SPONSOR 
Noxopharm Limited will conduct the study in all respects in accordance with the ethical 
principle of the current amendment of the Declaration of Helsinki and with ICH GCP regarding 
responsibilities of the Sponsor. Noxopharm Limited reserves the right to terminate the study 
at any time. A written explanation will be provided to the Investigator should the study be 
terminated. The Investigator is responsible to inform the HREC of such a decision and to 
return all study materials to the Sponsor. 
Noxopharm Study Manager:     Sujith Nayar 
 
 
 
 
   Telephone: +61 2 91442223 
 
 
 
 
   Email: Sujith.Nayar@noxopharm.com 
 
3.2 CONTRACT RESESARCH ORGANISATION 
Activities relating to the conduct and management of this trial may be delegated to Contract 
Research Organizations. All activities will be conducted in accordance with ICH GCP, with the 
overall responsibility for the study remaining with the Sponsor.  
 
3.3 INVESTIGATOR AND SITES 
This study will be conducted at oncology clinics across Australia, Georgia and New Zealand. 
Sites will be approved for participation by the applicable HREC, local and national authorities. 
By signing this protocol on behalf of his / her research institute, the Principal Investigator has 
agreed to undertake the responsibilities of conducting this clinical research study.  
 
3.4 MEDICAL OVERSIGHT 
Medical management and patient care while participating in this study is the responsibility of 
the Principal Investigator. Review of adverse events and decisions on continuation in trial, 
medical intervention and other related activities for an individual patient shall be at the 
discretion of the Principal Investigator. Review of adverse events and decisions on 
continuation in trial, medical intervention and other related activities for the overall study 
shall be at the discretion of the Study Steering Committee – consisting of Principal 
Investigators, an independent Oncologist and a representative of the Sponsor company.  
 


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4 INTRODUCTION 
The mainstays of oncology therapy – chemotherapy and radiation therapy – provide varying 
degrees of efficacy in patients with cancer, and for those with late stage metastatic disease 
the prognosis for patients can be very poor. A primary reason for these poor outcomes is the 
presence of chemo- and radio-resistance mechanisms in tumour cells.1 This resistance leads 
to higher doses of chemotherapy and/or radiation therapy being required, to a point where 
the adverse effects (toxicity) of therapy outweighing the benefits, or that treatment no longer 
provides any benefit for patients. Finding a treatment that can overcome some or all of these 
resistance mechanisms may lead to: 
• Providing therapy with clinically meaningful outcomes for patients with end stage and 
late stage cancers  
• Improving clinical outcomes for patients undergoing established chemotherapy and 
radiation therapy treatment 
• Allowing lower doses of chemotherapy and radiation therapy to be used in future 
treatment of patients, providing similar efficacy outcomes while minimizing toxicity – 
providing treatment for patients who may otherwise not receive treatment (e.g. frail 
and elderly patients) 
This study will investigate the use of NOX66 - idronoxil formulated in a lipophilic base – in 
combination with palliative radiation therapy, in patients with end stage castrate resistant 
prostate cancer. The data generated, in conjunction with other early phase studies, will be 
used to inform the development of larger studies to investigate the efficacy and safety of 
NOX66 (idronoxil) in combination with radiation therapy and chemotherapy. 
The key hypotheses to be tested in this study are: 
a. That idronoxil can be safely added to palliative dose radiation therapy. 
b. That idronoxil, via its selective inhibition of PI3K/Akt signalling in tumour cells, 
may sensitise tumours to palliative doses of radiation therapy, with efficacy 
signals being seen in this study.  
c. That any efficacy seen in irradiated tumours may lead to an effect on non-
irradiated tumours. 
Furthermore, this study will investigate three doses of NOX66 to determine if there is any 
difference in safety and / or efficacy signals with increasing dose and to determine the optimal 
dose for future radiation therapy combination studies.  
 
4.1 MULTI-DRUG RESISTANCE, CHEMO- AND RADIO-SENSITISATION AND 
IDRONOXIL 
Tumour cells develop a variety of mechanisms to avoid the effects of anti-cancer drugs. The 
term multi-drug resistance (MDR) refers to the typical situation where resistance to 


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treatment extends to most, if not all, chemotherapy drugs and treatment regimens. Some 
tumour cells display MDR from the outset (inherent resistance), while others develop it 
following exposure to chemotherapy (acquired resistance). Both forms of resistance are 
based on the same MDR mechanisms. 
A range of mechanisms are involved in MDR including: altered membrane transport, 
enhanced DNA repair, alteration of target proteins, activation of alternate signalling 
pathways, enzymatic digestion of drug, blockage of apoptosis, up-regulation of tumour-
promoter genes and down-regulation of tumour-suppressor genes.1-4 Of these, enhanced 
DNA repair also is an important mechanism in the resistance of tumour cells to radiation 
therapy.5,6 
Linking these various functions are a small number of upstream pro-survival pathways, 
particularly those regulated by phosphoinositide 3-kinase (PI3K), the serine/threonine kinase 
Akt, and the anti-apoptotic pathway NF-kB, all of which are over-expressed in many forms of 
cancer.6,7 
The key role of the PI3K/Akt/NF-kB signalling pathways in chemo- and radio-resistance 
mechanisms has marked them as key targets for drug development. These pathways, 
however, have an essential role in the survival of all cells, cancerous or otherwise6 - a 
fundamental that has blocked the successful development of any drug to target this pathway 
and provide selective targeting of cancer cells. The mechanism of action of idronoxil may 
overcome this barrier.  
Idronoxil is a small molecule synthetic derivative of the naturally-occurring isoflavone, 
genistein. Genistein has been shown to sensitise a range of solid cancer cells to both 
chemotherapy and radiation therapy, via both direct inhibitory effects on signal transduction 
and indirectly by genomic effects.8-11 Idronoxil has been specifically developed to enhance the 
anti-cancer properties observed with genistein by reducing the level of Phase 1 metabolism 
(and consequent loss of bio-activity) – leading to activity 10-30 times greater.12 
The mechanism of action of idronoxil means that it can selectively inhibit cancer cell PI3K/Akt 
pathways without affecting non-cancer cells. It does this by targeting an upstream regulator 
of PI3K/Akt which is expressed differently in cancer cells. Inhibition by idronoxil of this 
upstream target deprives the tumour cell of its key pro-survival signalling pathways, leading 
to down-regulation of PI3K/Akt. 
 
4.2 IDRONOXIL – A SELECTIVE INHIBITOR OF PI3K/AKT 
Idronoxil, also known as phenoxodiol, is a first-in-class, selective PI3K/Akt inhibitor. Details of 
the pharmacology of idronoxil are found the current version of the NOX66 Investigator’s 
Brochure. 
The primary target of idronoxil is external membrane NADH oxidase Type 2 (ENOX2). ENOX 
enzymes are located on the external membrane of cells and by regulating the movement of 


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electrons (protons) across the plasma membrane are responsible for maintaining the 
transmembrane electron potential.13 
Human cells have the capacity to express two forms of ENOX known as ENOX1 and its splice 
variant, ENOX2. ENOX1 is the constitutive form expressed by healthy cells while current 
literature suggests that ENOX2 is the active form of the ENOX enzyme in all cancer cells. 
Idronoxil binds to the motif that distinguishes ENOX2 from ENOX1, but has no binding affinity 
to ENOX1.14  
Inhibition of ENOX2 leads to an accumulation of protons within the plasma membrane of the 
cancer cell, creating a cascade of events involving the inhibition of a variety of downstream 
pro-survival pathways as described in Section 5.3. Because idronoxil selectively binds to 
ENOX2, with no binding affinity for ENOX1, only the cells expressing ENOX2 (i.e. tumour cells) 
are affected by idronoxil.15 
 
4.3 IDRONOXIL – SUMMARY OF MECHANISM OF ACTION 
The mechanism of action of idronoxil is summarized below, in Figure 1.  
 
Figure 1 Sequence of biochemical events following binding of idronoxil to ENOX2.  
The cascade of events is as follows:13-16 
1. Idronoxil binds to ENOX2, leading to inhibition of the trans membrane electron pump 
which, in turn, leads to an accumulation of proton ions within the plasma membrane.  


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2. Accumulation of protons disrupts sphingomyelin pathway with blockage of ceramide 
conversion to sphingosine-1-phosphate (S1P) – leading to a decrease in S1P and an 
increase in Ceramide within the plasma membrane.  
3. Decrease of S1P leads to a reduction in PI3K, AKT and XIAP and an increase in Caspase 
2.  
4. Reduction in AKT leads to reduction in NF-kB and allows up regulation of the intrinsic 
(mitochondrial) pathway of apoptosis, via an increase in Caspase 9 and Caspase 3, 
leading to cell death.   
5. Reduction in AKT also results in an inhibition of FLIP resulting in an increase in Caspase 
8 (activated via the Death Receptor on the Protein Membrane) – leading directly and 
indirectly (via the intrinsic pathway) to an increase in Caspase 3 and apoptosis. 
6. Reduction in XIAP prevents down regulation of Caspase 9 and Caspase 3, supporting 
apoptosis. 
Both in vitro and in vivo, idronoxil provides high levels of synergistic cytotoxicity with a wide 
range of chemotoxic (cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin) and 
chemostatic (topotecan) drugs across a broad range of cancer phenotypes.17-19 
Where the terms chemo-sensitisation and radio-sensitisation often are used in the sense of 
priming cells to undergo greater drug- or radiation-induced damage, idronoxil (as used in this 
study) acts to block the ability of tumour cells to repair and recover from damage caused by 
chemotherapy and radiation therapy. 
 
4.4 IDRONOXIL – INTRAVENOUS AND ORAL DOSAGE FORMULATION 
Following pre-clinical development, Idronoxil commenced a clinical development program in 
2000, for intravenous (IV) and oral administration. Between 2000 and 2009 a series of phase 
1 and phase 2 studies were conducted, with a multi-centre Phase 3 trial commenced to 
investigate oral idronoxil as a chemo-sensitiser of carboplatin in late-stage, chemo-refractory 
ovarian cancer cases.20 Over 400 patients with late-stage cancer were treated in Phase 1, 2 
and 3 clinical studies.21 The clinical development program was stopped during the phase 3 
program due to slow recruitment into the pivotal trial and no difference in efficacy between 
the treatment arms. Further information regarding previous studies is contained in the 
current NOX66 Investigator’s Brochure. 
 
4.5 IDRONOXIL – NOX66 DOSAGE FORMULATION 
The lack of efficacy observed in the Phase 2 and 3 trials of oral idronoxil with carboplatin has 
been attributed to a high level (> 99%) of metabolism. Idronoxil undergoes Phase 2 
metabolism within the body, whereby water-insoluble compounds are converted into more 


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water-soluble forms through the action of transferase enzymes (present in gut mucosa and 
liver). This is achieved by attaching a glucuronide or sulphate chemical group. The resulting 
water-soluble drug conjugate is biologically inactive, with reactivation requiring enzymatic 
digestion by glucuronidases and sulphatases present in the lysosomes of target cells. Many 
phenolic drugs undergo this process including aspirin, codeine, paracetamol, naloxone, 
propofol and steroid hormones. 
Most normal cells contain high levels of glucuronidases and sulphatases, accounting for the 
biological activity of other phenolic drugs. Recent studies, however, suggest that cancer cells 
amend or inhibit this function as one of their multi-drug resistance mechanisms. Breast cancer 
cells, for example, have been found to contain negligible levels of deconjugating enzymes,22 
while some other forms of cancer undertake their own Phase 2 (transferase) metabolism.23   
NOX66 is a suppository dosage form of idronoxil, formulated in a hydrogenated lipophilic base 
and developed specifically to reduce the exposure of the drug to Phase 2 metabolism. Rectal 
absorption is a standard method of drug administration where Phase 2 metabolism is sought 
to be minimized, with venous drainage from the distal part of the rectum feeding into the 
inferior vena cava, thereby avoiding first pass liver metabolism. The lining of the rectum also 
is largely devoid of transferase activity.24-26   
Rat studies conducted by Noxopharm27 have suggested that when administered rectally in the 
form of NOX66: 
• idronoxil is readily bioavailable  
• the degree of Phase 2 metabolism is reduced  
• the drug readily distributes within tissues 
• is excreted primarily via the urine 
• administered drug is largely eliminated within 24 hrs, with no evidence of 
accumulation. 
 
4.6 NOX66 – CURRENT DRUG DEVELOPMENT PROGRAM 
This study forms part of a program of phase 1 studies designed to provide insight in to the 
safety and signals for efficacy of NOX66 in various cancer therapy settings, namely: 
- 
Safety and PK of NOX66 as monotherapy 
- 
NOX66 in combination with chemotherapy alone 
- 
NOX66 in combination with palliative radiation therapy alone, and the effects on 
tumours externally targeted with radiation 
- 
NOX66 in combination with palliative radiation therapy alone, and the effects on 
tumours not targeted with radiation therapy 
- 
NOX66 in combination with radiation therapy alone, with radiation therapy being 
administered as brachytherapy (internal targeting of treatment) 
- 
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5 STUDY RATIONALE 
5.1 RATIONALE FOR COMBINATION WITH RADIATION THERAPY 
5.1.1 Radio-sensitisation 
Many cancer patients receive radiation therapy, either as part of a treatment regimen or in 
the palliative setting, to reduce tumour size and manage pain and symptoms associated with 
end stage cancer.28  
The anti-cancer effect of ionizing radiation relates to its ability to cause double strand breaks 
in DNA, and the non-specificity of this effect means that the dosage of radiation able to be 
applied is self-limiting. This dosage limitation is exacerbated by the presence of factors (radio-
resistance) that render some cancer cells less sensitive to the damaging effects of ionizing 
radiation, while normal cells are without those same factors and retain full radio-sensitivity, 
as discussed in Section 5.1. 
The use of NOX66 as a tumour cell-specific sensitiser of radiation therapy may provide greater 
response to targeted radiation therapy within the tumour cells, with the tumour specific 
nature of NOX66 activity leading to no greater effect on non-tumour cells. As such, NOX66 is 
expected to increase the response to palliative dose radiation therapy, reducing target 
tumour size beyond those expected with palliative radiation therapy alone, with no significant 
increase in serious and severe adverse events. 
5.1.2 Abscopal Response 
An abscopal (from Latin ab-scopus, away from the target) response describes tumour 
regression at sites distant to an irradiated field, and is a rare event seen in patients with 
various types of metastatic tumours receiving palliative radiation therapy to a single 
metastasis. First described29 over 50 years ago, the response is sufficiently rare to warrant 
clinical reports of individual cases, with responses in melanoma, lung cancer, kidney cancer 
and cutaneous lymphomas variously reported.30-33 
In the only prospective clinical study34 reported to date, 41 patients with metastatic solid 
cancers were treated with a combination of standard cytotoxic chemotherapy, external beam 
RT, and granulocyte-macrophage colony stimulating factor (GM-CSF). A maximum 2 lesions 
were irradiated (35 Gy in 10 fractionated doses) and the response measured by CT scan in 
both irradiated and non-irradiated lesions. An abscopal response was reported in 11/41 (27%) 
patients (4 lung cancer, 5 breast cancer, 2 thymic cancer). Two of these cases had a complete 
response (lung cancer) and 9 had a partial response. The median overall survival was 21 
months for abscopal responders versus 8 months for the non-responders.  
While the mechanism underlying this phenomenon is unknown, the results of the above 
study, in conjunction with a range of pre-clinical studies, points to the involvement of soluble 
signalling factors including tumour antigens that are hypothesized to be released by the dying 
irradiated tumour cells to mediate an immune response against non-irradiated lesions.35,36,37 


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In addition to its anti-cancer effects, idronoxil also has confirmed immune-stimulatory 
effects.38 Human peripheral blood CD56+ natural killer (NK) cells show increased lytic activity 
against K562 (myelogenous leukaemia cell line) in the presence of idronoxil. Also, in a mouse 
colon cancer (CT-26) model in which idronoxil monotherapy produced a significant anti-
cancer effect, ex vivo studies showed that idronoxil activated both NK and tumour-specific 
tumour cell lysis. As such, it is hypothesized that NOX66 may produce an abscopal effect in 
treating non-irradiated lesions when combined with radiation therapy. 
In this study, we will also monitor for any changes in non-irradiated lesions, to determine if 
NOX66 may induce an abscopal response when combined with radiation therapy. 
 
5.2 RATIONALE FOR DOSE OF NOX66 
Pre-clinical studies in mice consistently found an effective chemo-sensitising (standard 
cytotoxic drugs) dose of idronoxil to be between 100-150 mg/kg.12 Phase 2 metabolism in 
these models was observed to be significant, with 10-30% of idronoxil remaining as free drug 
and the remainder being excreted as the conjugated (inactive) metabolites. As such, an 
effective dose in rats of 20mg/kg free idronoxil has been used. This converts to an equivalent 
human dose of 3-4mg/kg, based on body surface area. Dosing in line with this was used for 
the intravenous and oral dosage formulations of idronoxil, with a dose of 1200mg being used 
for the Phase 3 oral study (Refer to Investigators’ Brochure for further information) 
Whilst the oral dose of idronoxil was found to be ineffective to due Phase 2 metabolism, these 
studies do show that idronoxil has minimal effect on non-tumour cells (in which 
deconjugation does occur and therefore the cells are exposed to active idronoxil). As such, 
doses in line with the oral dosing regimen have been selected for this and other phase 1 
studies. NOX66 has been developed to protect idronoxil from complete Phase 2 metabolism, 
enabling the active ingredient to target tumour cells and, in the case of this study, sensitise 
the target tumours to radiation therapy. 
While idronoxil displays significant anti-cancer effect in animals as a monotherapy,12,39 the 
applicants believe that its potential clinical use lies in its sensitizing abilities, which requires 
having the drug present in the tumour cell during the period of induction of the cytotoxic 
damage and the repairing process of that damage. 
 
5.3 POTENTIAL RISKS 
As with all products and formulations in Phase 1 development, the adverse event profile of 
idronoxil in the formulation of NOX66 has not been fully established.  
In vitro studies have shown no binding affinity for idronoxil to healthy human cells and, as 
such, minimal adverse events directly due to idronoxil are expected. This has been supported 


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by the clinical research program of IV and oral formulations of idronoxil, where no adverse 
events of toxicity Grade 2 or higher have been reported.  
It is expected that any adverse events observed in the study will be due to the use of the 
combination of NOX66 with palliative radiation therapy. Any adverse events greater than 
normally observed with this therapy in the patient group for this study (e.g. fatigue at level 
greater than Grade 2) are expected to be related to a greater efficacy of the treatment (due 
to the sensitizing effect of NOX66). 
 
5.4 POTENTIAL BENEFITS 
As a Phase 1 sighting Study, the efficacy (benefits) of combining palliative radiation therapy 
and idronoxil (NOX66) is not known. The hypothesis, however, is that the effect of idronoxil 
in sensitizing the cancer cells to radiation therapy will provide an enhanced response to this 
treatment, with a clinical response observed in the patients participating in the trial.  
 
 


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6 STUDY OBJECTIVES AND HYPOTHESES 
6.1 PRIMARY OBJECTIVE 
• To determine the safety and tolerance of idronoxil, administered as the NOX66 
formulation in escalating dose cohorts and concurrently with palliative radiation 
therapy, in patients with end stage castrate resistant prostate cancer. 
 
6.2 SECONDARY OBJECTIVES 
• To investigate whether idronoxil administered as the NOX66 formulation will sensitise 
end stage prostate cancer to palliative radiation therapy and provide a clinically 
relevant response to treatment according to: 
o RECISTv1.1 criteria for measurable lesions, within irradiated and non-
irradiated target lesions  
o Improvement in total pain scores using BPI-SF instrument  
o To observe changes in serum PSA  
o Review of CT/MRI scans by Radiation Oncology Expert Committee –assessment 
of observable and or symptomatic changes from baseline over time 
 
• To determine a dose of NOX66 to continue into late phase clinical trials 
• To investigate plasma idronoxil levels following NOX66 therapy  
• To determine Progression Free Survival (PFS) and Overall Survival (OS)  
 
 
 


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7 STUDY DESIGN 
This is an open-label Phase Ib dose confirmation and proof of concept study in up to 24 
patients with end stage castrate resistant prostate cancer who are being considered for or 
undergoing palliative radiation therapy for pain and symptom management.  Patients will 
have a minimum of one (1) lesion which is amenable to radiation therapy. Palliative RT (20Gy 
over 5 fractions) will be delivered to selected lesion in combination with rectally administered 
idronoxil (NOX66).  
This study is intended to provide information regarding the safety of this treatment 
combination and justification for a larger Phase 2/3 study in the treatment of patients with 
combination of NOX66 and palliative radiation therapy. 
Clinical response to treatment will be assessed by radiological CT/MRI scans, where applicable 
objectively measures by RECISTv1.1, by pain response as evaluated by Brief Pain Inventory 
Short Form, ECOG scores and by monitoring PSA as surrogate marker with overall (observable 
and symptomatic) response based on data review by an independent Radiation Oncology 
Expert Committee (ROEC). Local response will be based on investigator review of data in 
conjunction with ROEC.  
PSA will be monitored as a surrogate marker of response and pain response will be evaluated 
using the Brief Pain Inventory Short Form throughout the study.  
Patients will be suitable for the study as they become eligible for, and will be given, palliative 
radiation therapy for management of their cancer. 
Three dose cohorts will be investigated in this study with dosing based on criteria outlined in 
section 10.2.7. The three doses of idronoxil investigated include: 
- 
400mg idronoxil provided as one NOX66 suppository per day 
- 
800mg idronoxil provided as one NOX66 suppository twice daily 
- 
1200mg idronoxil provided as one NOX66 suppository three times daily. 
Treatment will be for one cycle of combined radiation therapy and NOX66 with follow up 
assessments at Week 6, Week 12, Week 24 and every 3 months for the following 18 months.  
All patients will be followed up for disease progression and survival information either by 
retrospective review of medical records or by a physical visit or by telephone follow up call.  
8 STUDY PARTICIPANTS 
8.1  STUDY POPULATION 
Twenty-four patients with metastatic castrate-resistant prostate cancer and scheduled to 
receive palliative radiation therapy for management of their disease will be enrolled into the 
study.  
There will be no randomization or stratification in the study. 


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8.2 INCLUSION CRITERIA 
Patients must fulfil all of the following inclusion criteria to be eligible to enrol into the study: 
1. Provision of informed consent.  
2. ≥ 18 years of age. 
3. Histologically confirmed prostate cancer and/or PSA of > 100 ng/mL at original diagnosis 
4. Metastatic disease evidenced by either CT/MRI imaging or bone scan. 
5. Objective evidence of disease progression as defined by either: 
i. Radiographic progression of in nodal or visceral metastases and bone disease 
progression with 2 or more new lesions  
ii. Rising PSA value ≥2ng/ml in at least 3 measurements, at least 1 week apart, with 
castrate levels of serum testosterone. 
6. Eligible to receive palliative radiation therapy to at least one symptomatic lesion for 
management of disease.  
7. ECOG Performance status 0-2.  
8. A minimum life expectancy of 24 weeks. 
9. Adequate bone marrow, hepatic and renal function as evidenced by:  
• Absolute neutrophil count (ANC) > 1.5 x 109/L  
• Platelet count > 100 x 109/L  
• Hemoglobin > 9.0 g/dL  
• Serum bilirubin < 1.5 x ULN  
• AST/ALT (SGOT/SGPT) < 2.5 x ULN for the reference laboratory or < 5 x ULN in 
the presence of liver metastases  
• Serum creatinine < 1.5 x ULN  
10. Ongoing androgen deprivation therapy with luteinizing hormone-releasing hormone 
(LHRH) agonist or antagonist.  
11. At least 4 weeks must have elapsed prior to commencement of NOX66 treatment since 
prior chemotherapy, investigational drug or biologic therapy and any toxicity associated 
with these treatments has recovered to ≤ NCI-CTCAE (version 4.03) Grade 1. 
12. At least 21 days must have elapsed following major surgery and any surgical incision 
should be completely healed. 
 
8.3 EXCLUSION CRITERIA 
Patients who have any of the following exclusion criteria are not eligible to participate in the 
study: 
1. 
Tumour involvement of the central nervous system  
2. 
Uncontrolled infection or systemic disease  


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3. 
Clinically significant cardiac disease not well controlled with medication (e.g. 
congestive heart failure, symptomatic coronary artery disease, angina, and cardiac 
arrhythmias) or myocardial infarction within the last 12 months 
• Patients with a QTc > 470 msec on screening ECG 
4. 
Concurrent systemic chemotherapy or biological therapy 
5. 
Any situation where the use of suppository therapy is contra-indicated or impractical 
(eg. chronic diarrhoea, colostomy, ulcerative colitis). 
6. 
Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously 
treated or both)  
7. 
Any subject whose testosterone is not suppressed i.e. is > 0.5nmols/L. 
8. 
Any other reason which, in the opinion of the investigator, will preclude suitable 
participation in the study. 
 
8.4 SCREEN FAILURE AND STUDY WITHDRAWAL 
Patients should begin protocol treatment within 2 weeks of enrolment at screening. Issues 
that would cause treatment delays longer than 2 weeks should be discussed with the Sponsor. 
If a patient does not proceed to receive protocol therapy following enrolment at screening, 
the patient’s study enrolment will be cancelled, and the patient will be considered a screen 
failure. The Sponsor should be notified of screen failures as soon as possible. 
Patients will be informed that they are free to withdraw from the study at any time and for 
any reason. Withdrawal criteria, other than progressive disease, can be defined as one or 
more of the following: 
• an inter-concurrent illness that prevents further administration of idronoxil (NOX66) 
or radiation therapy;  
• an adverse event to the combination treatment that is intolerable;  
• the patient withdraws consent;  
• the patient dies;  
• general or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the Investigator.   
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient’s 
medical records. The patient must be followed to establish whether the reason was an 
adverse event causally related to idronoxil (NOX66), and, if so, this must be reported in 
accordance with the requirements for adverse event reporting. 
Patients will continue to be followed for the duration of the study, unless consent is 
withdrawn.  
 


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8.5 PATIENT REPLACEMENT 
Patients who cannot be evaluated as part of the efficacy analysis may be replaced in the study 
at the discretion of the Sponsor. 
 
9 STUDY MATERIALS 
9.1 INVESTIGATIONAL STUDY PRODUCT 
9.1.1 Description and Formulation 
The active drug substance, idronoxil, is manufactured by chemical synthesis and is produced 
as a single monomer. Idronoxil is manufactured to > 98% purity.  
Nomenclature 
Codename:  
 
Idronoxil 
Chemical Name:  
2H-1-Benzopyran-7-0,1,3-(4-hydroxyphenyl) 
Other names:    
Dehydroequol  
Empirical Formula:   C15H12O3  
Molecular Weight: 
240.26 g/mol 
NOX66 is idronoxil in a suppository dosage form for rectal delivery. The drug substance, 
idronoxil, is formulated in hydrogenated lipophilic base to yield suppositories with an 
approximate weight of 2.2 g and containing 400 mg drug substance.  
 
9.1.2 Presentation, Storage and Handling 
Presentation: NOX66 is presented as a solid dosage form as a suppository for rectal delivery.  
NOX66 is presented in plastic sleeves in boxes. Each box contains 16 suppositories. Patients 
will be provided with 1, 2 or 3 boxes, depending on which cohort they are enrolled into.  
NOX66 investigational product will be provided directly by the Sponsor to the clinical trials 
centres. 
Storage and Handling: NOX66 boxes should be stored at the study centre in a secure area with 
limited access at 2-8°C (refrigerated) and protected from light. Any breach of investigational 
product storage conditions should be notified to the Sponsor on detection and the medication 
should be quarantined until the Sponsor authorizes usage or otherwise. 
NOX66 is not expected to pose any safety risks to the Investigational staff under normal 
conditions of storage and distribution. Idronoxil has the lowest grade (Grade 4) of hazard 
classification (according to Regulation (EC) No. 1272/2008 [EU-GHS/CLP) with an acute oral 


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toxicity of between 300 to >2000 mg/kg body weight. The product also is contained within 
air-tight plastic moulding. 
 
9.1.3 Labelling 
Each box will be labelled with: 
• the name of the Sponsor and address;  
• the study protocol number;  
• pharmaceutical dosage form, quantity of dosage units;  
• name and strength of the product;  
• the batch/lot number of the contents;  
• period of use (expiry date or re-test date as applicable) in month/year; 
• Caution Statement: "Caution: Clinical Trial Use Only; Keep out of reach of children.";  
• storage instructions; 
• PI name; 
• Patient ID. 
Each suppository will be labelled with: 
• the name of Sponsor; 
• the study protocol number; 
• pharmaceutical dosage form, quantity of dosage units;  
• name and strength of the product;  
• the batch/lot number of the contents. 
Boxes (plus any remaining contents) are to be accounted for. 
9.1.4 Procurement and Distribution 
NOX66 investigational product will be provided directly by the Sponsor. 
Patients are to be given their NOX66 treatment following confirmation of eligibility 
(screening) and the scheduled commencement of treatment.  
Patients to return medication following completion of NOX66 therapy for drug accountability. 
 
9.2 INVESTIGATIONAL PRODUCT ADMINISTRATION 
Idronoxil in the form of a suppository (NOX66) will be self-administered once, twice or three 
times daily depending on the patient cohort allocation and continue for up to 16 days.   
Dosing will commence on the day prior to RT, continue daily during RT (including days in which 
RT is not given) and 7 days post RT completion.   
Patients will be instructed on the method of administration and provided with an instruction 
sheet. 


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The drug can be administered at any time during the day, but the same time should be used 
each day. Twice daily doses should be administered at approximately 8 to 12hour intervals 
and for three times daily dosing, first dose to be administered in the morning and two doses 
administered should be administered at approximately 8-12 hours later. A missed dose should 
be taken as soon as it is noted as missed. Taking two suppositories at the same time is 
permitted in order to catch up a missed dose within a day. No more than three suppositories 
should be taken in a 24-hour period. 
 
9.3 RADIATION THERAPY 
External beam radiation therapy will be applied to a minimum of one or more selected lesions 
in 5 daily fractions, over five to eight days, at a dose of 20Gy.  
The number of lesions to be irradiated will be at the discretion of the investigator as clinically 
indicated. Lesions which directly receive radiotherapy will be categorized as “irradiated 
lesions” with all other lesions identified as “non-irradiated lesions”.  
Lesions will be assessed by the investigational site at screening and any symptomatic lesion/s 
for irradiation which can be assessed by RECIST 1.1 criteria will be noted as “measurable 
irradiated target lesions” and symptomatic lesions that cannot be measured will be noted as 
“non-measurable lesions”. Further detail is provided in Section 10.4.8. Lesions will be 
captured by CT or MRI scan at baseline with follow-up CT/MRI imaging at Week 6, Week 12 
and Week 24. Scan image data will be stored on central planning system software (such as 
MIM) for radiological comparisons and response to treatment will be reported. 
During screening period, baseline lesion/s will be selected for irradiation and the gross 
tumour volume (GTV), the clinical target volume (CTV) and organs at risk (OAR) will be defined 
by the radiation oncologist based ICRU 50 or ICRU 83 guidelines.  
Radiation therapy will be delivered to target labelled irradiation lesions according to the study 
radiation treatment plan developed. Details are provided in the NOX66-002A Radiation 
Therapy Planning, Delivery and QA Guidelines which must be used as the primary source for 
planning and delivering radiation therapy treatment within the trial. 
Tumour lesions either for irradiation or not which, at baseline, are identified as measurable 
will be noted as target lesions and will be assessed for response to treatment according to 
RECIST 1.1 criteria. Symptomatic tumour lesion which at baseline is identified for irradiation 
but not measurable will be noted a non-measurable target lesion/s. 
All radiological scans during the study will be reviewed by the independent Radiation 
Oncology Expert Committee for each patient to assess overall response to treatment. 
 


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9.4 TREATMENT DOSE MODIFICATIONS AND TREATMENT CYCLE DELAY 
9.4.1 NOX66 
Any patient who experiences toxicity > Grade 2 related to NOX66 will have the idronoxil 
treatment withheld for 1 day and then resume on the next lower dosage (1200 mg reduced 
to 800 mg; 800 mg reduced to 400 mg; 400 mg daily reduced to 400 mg every 2nd day) for the 
remainder of the treatment period.  
If toxicity > Grade 2 persists following reduction of dose, the idronoxil treatment will cease 
immediately for the remainder of the treatment period, although the patient may remain in 
the study.  
There will be no dose modification of NOX66 on the basis of body weight.  
9.4.2 Radiation Therapy 
There will be no dose modification of radiation therapy. Any deviation from the planned dose 
of radiation therapy will be reported by the investigator in the CRF.  
 
9.5 ACCOUNTABILITY FOR CLINICAL SUPPLIES 
The Principal Investigator or delegate/s will be responsible for the dispensing, inventory, and 
accountability of all clinical supplies, exercising accepted medical and pharmaceutical 
practices. An accurate and timely accountability record log of the disposition of all clinical 
supplies must be maintained. The supplies and inventory record must be made available for 
inspection by the Sponsor or the designated Sponsor’s representative upon request. All used 
medication packaging and unused medication will be collected and retained until completion 
or termination of the study. Once all drug accountability has been performed and monitored 
the Investigator or delegate/s will destroy NOX66 as per Site Pharmacy SOPs and/or return all 
remaining clinical supplies to the Sponsor who will destroy the study drug on the site’s behalf. 
Under no circumstances will the Principal Investigator allow NOX66 to be used other than as 
directed by this protocol. 
 
9.6 CONCOMITANT MEDICATIONS 
Patients are permitted a wide range of medications for general health, although this is to be 
confirmed with the Sponsor prior to enrolment into the Study. 
Patients are permitted certain medications specifically related to their metastatic disease, 
including use of androgen deprivation therapy (ADT) such as luteinizing hormone-releasing 
hormone (LHRH) agonists and antagonists. Other therapies are to be confirmed with the 
Sponsor medical monitor prior to enrolment in the Study.  


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Patients are not permitted any other experimental treatments. Supportive care measures and 
treatment for symptom control are permitted, including analgesics. Treatment of 
constipation or diarrhea is permitted however the investigator must determine the suitability 
of these patients to continue taking suppositories should these adverse events (as scored by 
NCI CTCAEv4.03) be reported. Patients will be medically monitored so that any adverse events 
will be identified promptly and treated appropriately.  
Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken within 14 days prior to study drug administration will be recorded in the 
eCRF at the Screening Visit and Day 1. Details regarding the name, indication, route of 
administration, dose, and frequency of all medications taken during the study will be recorded 
in the eCRF at each patient visit. “All medications” should include prescription, over-the-
counter (OTC) medications, dietary/nutritional supplements, and herbal products. 
 
10 STUDY PROCEDURES 
10.1 OUTCOME MEASURES 
The outcome measures supporting the primary objective of this study are:  
• Number of events of > Grade 2 toxicity (as scored by CTCv4.03) 
• Number of events of > Grade 2 toxicity considered by the investigator and / or the 
Sponsor as causally related to the use of NOX66 (as scored by CTCv4.03) 
• The overall number of adverse events considered by the investigator and / or the 
Sponsor as causally related to the use of NOX66 
• Incidence of dose limiting toxicities (DLT) and or maximum tolerated dose (MTD) of 
NOX66 
The outcome measures supporting the secondary objectives of this study are:  
• Where target (measurable) lesions have been identified: 
a. Change intumour size of irradiated lesions according to RECIST1.1 criteria, as 
assessed by central review and by the investigator based on CT/MRI scan  
b. Change in tumour size of target non-irradiated lesions according to RECIST1.1 
criteria, as assessed by central review and by the investigator based on 
CT/MRI scan  
c. Observation of change from baseline in Non-target lesions according to 
RECIST 1.1 criteria 
• For all patients – overall assessment of change in disease state by an independent 
Radiation Oncology Expert Committee 
• Change from baseline in pain score based on responses to BPI-SF   
• Observation of change from baseline in PSA levels  
• Assessment of patient via physical exam and ECOG Score 


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• Plasma level of idronoxil post treatment (immediate and long term (at 6 weeks)) 
• Duration of tumour progression free state from study treatment start date 
• Duration of survival from study treatment start date 
10.2 STUDY VISITS 
The total study duration per patient will be a minimum of 25 weeks, with continued follow up 
up to 24 months from the treatment commencement date:  
• Screening period: to occur within 2 weeks prior to the scheduled date of treatment 
commencing 
• Treatment and follow up period: up to 24 weeks from the commencement of the first 
dose of NOX66 and it includes enrolment visit to occur prior to Day 1 of treatment 
Long term follow up visits: every 3 months from week 24 for another 18 months. 
Observation period (post study follow-up visits): Continued observation of patients 
beyond 24 months follow up visit, at the discretion of the investigator.  
10.2.1  Screening Visit (VS) 
The purpose and the procedures of the Study will be fully explained to participants at the 
screening visit and every patient approached regarding the study will be provided with the 
Informed Consent Form (ICF). Patients wishing to enrol in the Study will sign the ICF prior to 
initiating any study related investigations or procedures.  
All screened patients who sign the ICF must be recorded on the Screening/Enrolment Log. If 
a patient who signs an ICF is not enrolled in the study, the reason will be noted. The 
Screening/Enrolment Log will be retained within the Investigator Site File. 
The following procedures are to be performed at the screening visit to occur within 2 weeks 
of commencement of NOX66 treatment: 
• Obtain Informed Consent 
• Review and confirm eligibility (Inclusion / Exclusion Criteria) 
• Medical History and Demography, including review of any prior radiation therapy and 
toxicities / adverse events 
• Physical Examination including vital signs 
• Performance Status Assessment (using ECOG performance scale) 
• Safety blood sampling – Complete Blood Count, Serum Chemistry, and Urinalysis; and 
results within 5 days of enrolment 
• Blood sample for serum PSA and testosterone 
• Electrocardiography (12-lead) in triplicate 
• Concomitant Medication Review 
• Tumour Imaging (CT/MRI) including measures of target lesions- baseline 
• Administration of Brief Pain Inventory -Short Form questionnaire 
 


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Radiological scans performed prior to consent may be utilized for the purposes of the study 
if they have been performed as part of routine clinical practice and the patient consents for 
their medical records to be reviewed by the Sponsor, the scans were performed in the 28 days 
prior to the screening visit (i.e. they can be considered current evidence of tumour size) and 
they can provide suitable tumour measurements and assessments of target and non-target 
lesions. 
The Principal Investigator will maintain a confidential log of all patients who have been 
screened for participation in the study whether or not the patient was eligible for study 
participation 
 
10.2.2 Enrolment Visit (V1):  
Once eligibility is confirmed patients will be contacted to attend clinic for: 
• education on self-administration and dispensing of NOX66 for use from Day 1 of the 
treatment cycle 
• baseline biomarker blood sample for idronoxil 
  
Patient may be contacted by telephone after enrolment as a reminder to start NOX66 
administration day prior to attending clinic for radiation therapy. 
 
10.2.3 Treatment Cycle (Days 1-16) - Visits 2 to 7  
Treatment will Commence on Day 1 of the Study Visit Schedule (Table 1) and the procedures 
for Treatment Visits are listed below in Table 1.  
Overall, the patient will attend the clinic on 7 days during the Treatment Cycle. 
During the Treatment Cycle, the patient will receive treatment of:  
• NOX66 (Dose dependent on treatment cohort) for 13 up to 16 consecutive days (Days 
1-16), inclusive of weekends and public holidays. 
• Palliative radiation therapy (20Gy Dose) in five fractions over 8 days commencing on 
Day 2 to Day 9. Radiation therapy not given on weekends and public holidays. 
 
 
 


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Table 1. Schedule of Assessments: TREATMENT CYCLE  
Period 
Pre-RT 
RT 
Post RT 
EoT3 
 
D0 (-7) 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D11 
D 12 
D 13  
D 14 
D 15 
D 16+1 
VISITS 
V11 
 
V2 
V3 - V62 
 
 
 
 
 
 
V7 
NOX66 (Self-administration) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
Radiation therapy 
 
 
X 
X 
 
 
 
 
 
 
 
Physical exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Complete Blood Count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biomarker5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BPI-SF6 Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications/ 
Adverse Event7 review 
 
 
X 
X 
 
 
 
 
 
 
X 
Dispense NOX66 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return NOX66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1Enrolment-Visit to occur after eligibility confirmation (Screening) and prior to V2, to receive NOX66 and education on self-administration   
2 Patient attend clinic for 5 days in an 8-day period to receive RT. Patient will not attend clinic on days where RT is not conducted 
3 End of Treatment (EoT) visit to occur Day following last dose of NOX66 
4NOX66 dosing continues to Day 16 if there has been (weekend and public holiday -up to 3 days) interruption in RT in Treatment Cycle. 
5 Biomarkers include idronoxil 
6 Brief Pain Inventory-Short Form (1991) 
7 Adverse Event (AE) assessed by Investigator using the NCI CTCAE v4.03 scoring system


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10.2.4 Six-Week Follow up (Day 43 ± 5) - Visit 8 
Visit 8 will occur 28 days/4 weeks post completion of NOX66 treatment and consist of the 
following assessments:  
• Physical Examination including vital signs 
• Performance Status Assessment (using ECOG performance scale) 
• Safety blood sampling – Complete Blood Count, Serum Chemistry and Urinalysis 
• Biomarker blood sampling – PSA and idronoxil  
• Administration of Brief Pain Inventory -Short Form questionnaire 
• Concomitant Medication Review 
• Adverse Event Review (CTCAE 4.03) 
• Tumour Imaging (CT/MRI scan) and Assessment 
 
10.2.5 Twelve-Week Follow up (Day 84 ± 7) - Visit 9 
Visit 9 will occur 70 days/10 weeks post completion of NOX66 treatment and consist of the 
following assessments:  
• Physical Examination including vital signs 
• Performance Status Assessment (using ECOG performance scale) 
• Electrocardiography in triplicate 
• Safety blood sampling - Complete Blood Count, Serum Chemistry and Urinalysis 
• Biomarker blood sampling – PSA 
• Administration of Brief Pain Inventory -Short Form questionnaire1 
• Concomitant Medication Review 
• Adverse Event Review (CTCAE 4.03) 
• Tumour Imaging (CT/MRI scan) and Assessment 
 
1 If pain score from assessment of response to BPI-SF questionnaire demonstrates an improvement in 
pain (refer to section 10.4.5) a confirmatory questionnaire at least 2 weeks later will be verbally 
administered to patients as described for 18-week administration of BPI-SF. 
 
10.2.6 Eighteen -Week administration BPI-SF (Day 125 ± 5) 
The Brief Pain Inventory- Short Form questionnaire will be verbally administered to patients 
by site staff via the telephone. Site staff will schedule a suitable time with the patient to 
conduct the phone interview and document patient responses.  
 
10.2.7 Twenty-Four Weeks Follow up/ end of study (Day 168 +7) -VISIT 10 
Visit 10 will occur 154 days/22 weeks post completion of NOX66 treatment and consist of the 
following assessments:  


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• Physical Examination including vital signs 
• Performance Status Assessment (using ECOG performance scale) 
• Electrocardiography in triplicate 
• Safety blood sampling - Complete Blood Count, Serum Chemistry and Urinalysis 
• Biomarker blood sampling – PSA 
• Administration of Brief Pain Inventory -Short Form questionnaire 
• Concomitant Medication Review 
• Adverse Event Review (CTCAE 4.03) 
• Tumour Imaging (CT/MRI scan) and Assessment 
 
All patients currently in the study or follow up period, will be asked to re-consent with the 
revised ICF in order to agree to participate for additional follow up visits (Visit 11 to 16).  
For patients who have withdrawn from the study prior to study completion or completed End 
of Study visit (Visit 10) at the time of this amendment implementation, the investigator or 
designee will make contact by phone to seek patient willingness to participate in long term 
follow up and if the patient agrees, a visit will be scheduled for reconsenting.   
For Patients who have completed End of Study Visit (Visit 10) at 24 weeks and are unable to 
be contacted or are > 6 months post EOS, the Investigator or designee at each study site will 
review medical records from End of Study visit to most recent information available and 
report on: 
• Disease status based on available radiology or other assessments 
• Patient Survival information 
• Any new anti-cancer treatment after discontinuation of study treatment 
10.2.8 Month 9 Long Term Follow up -Visit 11  
Visit 11 will occur approximately 3 months after 24 weeks follow up (Visit 10) and consist of 
the following assessments: 
• Performance Status Assessment (using ECOG performance scale) 
• Biomarker blood sampling – PSA 
• Administration of Brief Pain Inventory -Short Form questionnaire 
• Tumour Imaging (CT/MRI/US scan) and Assessment 
•  Report of any pain medication and any anti-cancer treatment after discontinuation 
of study treatment 
 
10.2.9 Month 12 Long Term Follow up -Visit 12 
Visit 12 will occur approximately 6 months after 24 weeks follow up (Visit 10) and   
consist of the following assessments: 
• Performance Status Assessment (using ECOG performance scale) 


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• Biomarker blood sampling – PSA 
• Administration of Brief Pain Inventory -Short Form questionnaire 
• Tumour Imaging (CT/MRI/US scan) and Assessment 
• Report of any pain medication and any anti-cancer treatment after discontinuation 
of study treatment 
 
10.2.10  Month 15 Long Term Follow up -Visit 13 
Visit 13 will occur approximately 3 months after the previous visit and consist of the following 
assessments: 
• Biomarker blood sampling – PSA 
• Tumour Imaging (CT/MRI/US scan) and Assessment  
• Report of any pain medication and any anti-cancer treatment after discontinuation of 
study treatment 
 
10.2.11  Month 18 Long Term Follow up -Visit 14 
Visit 14 will occur approximately 3 months after the previous visit and   
consist of the following assessments: 
• Biomarker blood sampling – PSA 
• Tumour Imaging (CT/MRI/US scan) and Assessment 
• Report of any pain medication and any anti-cancer treatment after discontinuation 
of study treatment 
 
10.2.12  Month 21 Long Term Follow up – Visit 15 
Visit 15 will occur approximately 3 months after the previous visit and   
consist of the following assessments: 
• Biomarker blood sampling – PSA 
• Tumour Imaging (CT/MRI/US scan) and Assessment 
• Report of any pain medication and any anti-cancer treatment after 
discontinuation of study treatment 
 
10.2.13  Month 24 Long Term Follow up -Visit 16 
Visit 16 will occur approximately 3 months after the previous visit and   
consist of the following assessments: 
• Biomarker blood sampling – PSA 
• Tumour Imaging (CT/MRI/US scan) and Assessment 


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• Report of any pain medication and any anti-cancer treatment after discontinuation 
of study treatment 
Patients who have disease progression during any of the follow up periods between Visit 10 
and Visit 16, will be followed up for survival information by the Investigator or designee via a 
telephone contact.  
 All data collected from Visit 11 to 16 will be entered in a paper CRF provided by the Sponsor 
or delegate.  
 
10.2.14  Cohort Allocation and Dose Escalation 
This study will enrol up to 24 patients across three dose levels of NOX66. Dose cohort 
assignment will be sequential and dose escalation decisions will be based on patients who 
experience adverse events directly related to NOX66 treatment and discontinued as 
described below and outlined in Figure 2. 
Dose escalation and decision rules are as follows: 
• Patients 1-4 (Dose Cohort 1) will be prescribed NOX66 400mg.  
 
• Patients 5-8 (Dose Cohort 2): Once fourth patient in Cohort 1 has completed 
treatment (Visit 7), the dose of NOX66 for next cohort, patients 5-8, will be as 
determined as follows, based on the number of discontinuations due to NOX66 
related adverse events: 
o If no patients discontinue treatment, NOX66 dose will be increased to 800mg 
o If one patient discontinues treatment, NOX66 dose will remain at 400mg 
o If more than one patient discontinues treatment, there will be no further 
recruitment to the study until scans from WEEK 6 are assessed for disease 
status 
  
• Patients 9-12 (Dose Cohort 3): Once the eighth patient in Cohort 2 has completed 
treatment (Visit 7), the dose of NOX66 for next cohort, patients 9-12, will be as 
determined as follows, based on the number of discontinuations due to NOX66 
related adverse events: 
o If no patients in Dose Cohort 2 discontinue treatment, NOX66 dose will be 
increased (from 400mg to 800mg or from 800mg to 1200mg) 
o If one patient in Dose Cohort 2 discontinues treatment, NOX66 dose will 
remain at the same dose (400mg or 800mg) 
o If more than one patient in Dose Cohort 2 discontinues treatment, dose will be 
reduced (from 800mg to 400mg) or, if dose has remained at 400mg, there will 
be no further recruitment to the study until scans at WEEK 6 are assessed for 
disease status.  
 


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Following the review of all accumulated safety data, disease status and treatment efficacy 
signals from scans assessed per RECIST 1.1 criteria and preliminary pain response at WEEK 6 
for all patients, the Study Steering Committee will determine the dose at which to continue 
treatment for the expansion patient Cohort 4 in the study. A further 12 patients will be 
recruited at this dose level.  
 
 
Figure 2: Dose Escalation and Dose Expansion Schema 
 
 
 
10.3 POST STUDY OBSERVATION 
After 24-month long term follow up, the investigator may report any changes in outcomes for 
patient specifically related to:  
• Progression of disease or relapse  
• Survival information 
 
 
10.4 CLINICAL ASSESSMENTS 
10.4.1 Medical History and demography 
Medical history will include demographic data (e.g., date of birth, race/ethnicity) and 
additional relevant medical information including:  


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• all medical conditions and disease states that require current or ongoing therapy, 
and  
• other medical conditions and disease states that, in the opinion of the Investigator, 
are relevant to the patient’s study participation 
 
10.4.2 Physical examination 
The physical Examination performed in this study will include  height, weight, blood pressure, 
pulse and body temperature and a physical (external) assessment of the patient. Blood 
pressure and pulse may be measured whilst the patient is sitting or lying but must be 
measured consistently for the patient throughout the study. Temperature should be 
measured in accordance with the centre’s standard practice. Any significant abnormalities 
noted during the physical examination at screening should be reported in the Medical History. 
Any significant changes noted on follow up physical examination should be reported as 
adverse events.  
10.4.3 ECOG Performance assessment 
A patient’s performance Status will be assessed using the Eastern Co-operative Oncology 
Group (ECOG) Performance Score (Appendix 1).   
10.4.4 Electrocardiography 
12-lead ECGs will be taken using a serviced and calibrated machine in triplicate, within 5 
minutes of each other (over 15 minutes), to calculate the mean QTc value to ensure the 
patients eligibility for study enrollment. ECGs should be taken after the patient has been 
resting supine for 5 minutes. 
ECG will be performed at three timepoints throughout the study – Screening, End of 
Treatment visit and end of study. Any abnormalities noted during the physical examination at 
screening should be reported in the Medical History. Any changes noted on follow up ECG on 
should be reported as adverse events. 
10.4.5 Brief Pain Inventory-Short Form 
Pain will be evaluated using the Brief Pain Inventory-Short Form instrument (Appendix 2). 
Total score is an average of the pain interference score (mean value for the nine BPI-SF items) 
and pain subscale score (mean value for the nine BPI-SF items 3,4,5 and 6).  
Questions on pain interference inquiring about extent of interference with activities by pain 
on scale of 0 (does not interfere) to 10 (completely interferes). 
Questions on pain inquire about extent of pain on scale of 0 (no pain) to 10 (pain as bad as 
you can imagine). 
Total score ranges from 0 to 10 with higher values indicating more pain. 
The BPI-SF questionnaire will be administered at six timepoints throughout the study- 
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Overall pain improvement response is defined as a decrease in pain score greater or equal to 
30% at 12 weeks relative from baseline without overall increase in opiate use and confirmed 
at least 2 weeks later per PCWG3 guideline41. 
 
10.4.6 Safety Blood Sampling 
Non-fasting samples for clinical laboratory analysis will be collected as listed below:  
• Complete blood count (CBC) including: white blood cells with differentials, red blood 
cells, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular 
haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet 
• Serum chemistry panel including sodium, potassium, calcium, creatinine, total 
protein, albumin, bilirubin (total, direct), AST/SGOT, ALT/SGPT, alkaline phosphatase 
(ALP) 
• Urinalysis dipstick - Clarity, specific gravity, pH, protein, glucose, ketones, nitrite, 
leukocytes, and blood.  Urine microscopy will be performed if urinalysis values are out 
of range and the Investigator deems that the microscopy is clinically warranted 
Haematology, clinical chemistry and urinalysis will be performed by the site’s local 
accredited laboratories. 
10.4.7 Biomarker Sampling    
• PSA levels will be collected at baseline, and post treatment cycle at Visit 8 (Day 43), 
Visit 9 (Day 84) , Visit 10 (Day 168) and Visit 11 – Visit 16 (every 3 months after Visit 
10) to determine any response to treatment. PSA samples will be collected by 
standard practice and analysed at each site’s local laboratory. 
Idronoxil: Plasma samples will be collected at baseline and Visit 7 (Day 16+1) of 
treatment cycle and post treatment at Visit 8 (Day 43) to determine levels of any 
accumulation during and post treatment.   Instructions for idronoxil plasma collection 
will be provided by Sponsor and analysis will be undertaken by the Sponsor performed 
by a designated laboratory. 
10.4.8 Tumour Imaging 
Tumour imaging by CT/MRI will be performed in line with local practices using a planning 
software system.  
Baseline documentation of Target and Non-Target lesions 
‘Target’ lesions are assessed at the designated scanning time points and defined as lesions 
that are measurable and: 
Irradiated, such as soft tissue and lytic bony lesions, have defined margins for 
measurement and are irradiated at the discretion of the investigator. These lesions 
will be noted as ‘irradiated measurable target’. 
• Non-irradiated and these lesions will be noted as ‘non-irradiated measurable target’.  


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For measurable lesions, the Longest Diameter (LD) of each lesion will be measured and a sum 
of the LD will be calculated and reported as the baseline sum LD. The sum LD will be used as 
reference by which to characterize the objective tumour response based on RECIST v1.1 
criteria (see below). 
Patients will undergo baseline CT or MRI body scan. A maximum of 5 lesions in total, with no 
more than 2 lesions per organ, will be identified as target lesions.  
 ‘Non-Target’ lesions include all other lesions and are recorded at baseline as either 
measurable or non-measurable. For non-measurable lesions, the presence or absence of each 
will be noted throughout follow-up scanning time points. For measurable lesions, size (mm) 
will be noted throughout follow-up scanning time points. 
These can include irradiated lesions such as sclerotic bone lesions, which do not have defined 
margins for measurements and are irradiated at the discretion of the investigator. These 
lesions will be assessed for local response based on patient reported outcome using the BPI-
SF (see section 10.4.5). 
Review of all CT/MRI scans per patient will be conducted by the independent Radiation 
Oncology Expert Committee as outlined in Section 10.4.9. 
 
RECIST evaluation of target lesions 
Assessment of irradiated measurable lesions will be conducted according to the RECIST1.1 
Criteria for response on the CT or MRI scan, as set out below.  
Complete Response (CR): 
Disappearance of all relevant target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of relevant target lesions, 
taking as reference the baseline sum LD 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of relevant target lesions, 
taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions. 
 
Evaluation of non-target lesions 
Non-measurable Assessment: 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumour 
marker level 


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 Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumour marker level above the normal limits 
Progressive Disease (PD):  
Appearance of one or more new lesions and/or unequivocal  
progression of existing non-target lesions. 
Measurable Assessment: 
Response  
Percent change in lesion size based on sum LD (mm) taking as reference 
the baseline sum LD.  
 
10.4.8.1 Radiological assessment of tumours during long term follow up period 
(Visit 11-16)   
Radiological assessments will be at the discretion of the investigator.  The disease status 
assessment will be based on local radiology results. No central radiographic assessment will 
be undertaken during the long term follow up period.  
 
10.4.9 Radiation Oncology Expert Committee 
A Radiation Oncology Expert Committee (ROEC), comprising medical Oncologists, Radiation 
Oncologists and Radiologists independent of the study sponsor, will be formed to assess 
clinical progression of patients on the study. The ROEC will receive copies of all CT/MRI scans 
(including any with RECIST measures), PSA measures, ECOG and pain score measurements for 
review and provide an assessment of overall clinical evaluation of response per patient which 
will be documented according to sponsor guidelines. This assessment will be used to support 
the definition of endpoints for future studies. 
 
11 DATA COLLECTION AND MANAGEMENT 
11.1 METHODS 
It is the responsibility of the Principal Investigator to ensure that there will be primary source 
documentation for all patient data collected as part of the study, and the data will not be 
recorded onto the eCRFs without the availability of such primary documentation. For this 
study, there is no data which has been permitted for direct data entry without source 
documentation. The source data may include such documents as clinical notes, laboratory 
result sheets, pathology reports, radiology results, etc., and will be retained in each patient’s 
medical record or research chart. CRFs will be provided by the Sponsor. 
The Principal Investigator or delegate/s will be responsible for the timeliness, completeness, 
and accuracy of the information entered on the CRF. The Principal Investigator will provide 


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access to the Medical Monitor or designated Sponsor representative(s) for the periodic 
review of all study records, source documents among other records for review and inspection 
to assure accuracy and completeness of the CRFs. All CRFs will be 100% source verified against 
corresponding source documentation (e.g., office and clinical laboratory records) for each 
patient. 
The Sponsor and designated Sponsor representative(s) will maintain frequent contact with 
each site to assure the study is conducted according to the protocol and that all data collected 
are accurate and complete. Any deficiencies identified during the study will be communicated 
to the site for prompt correction. 
11.1.1 Case report form 
All information relative to the study will be recorded into a 21 CFR part 11 FDA compliant 
electronic Case Report Form (CRF).  Data corrections will be entered by the authorised site 
personnel. 
11.1.2 Return and storage of forms 
The Investigator will retain the copies of the CRF and all other study related documents for 
15 years from completion of the study. 
 
11.2 DATA MANAGEMENT 
11.2.1 Data Coding 
Medications will be coded from the WHO Drug Dictionary and medical history and adverse 
events will be coded using the MedDRA terminology for System Organ Class (SOC) and 
Preferred Term (PT). 
11.2.2 Data validation 
A Data Management Plan which fulfils the requirements for ICH GCP will be developed to 
describe all manual and electronic validation checks of the data prior to analysis. Data queries 
requiring clarification will be documented on the EDC eCRF for the investigational site to 
resolve. Only authorised personnel will make corrections to the clinical database, and all 
corrections will be documented in an electronic audit trail.  
12 STATISTICAL SECTION 
12.1 SAMPLE SIZE 
The study is intended as a Proof of Concept and dose confirmation study, providing 
justification for and guidance on the design of further studies. 
The primary objective of this study is to observe safety and tolerability of idronoxil (NOX66) 
in combination with radiation therapy (at palliative doses). In conjunction with observations 


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from the other phase 1 trials in the NOX66 development program, 24 patients are considered 
adequate to inform on toxicity and safety in order to progress to phase 2/3.   
Palliative Radiation therapy alone is unlikely to provide more than a minor and temporary 
reduction (<30%) in tumour size. Any responses greater than this will be considered to be 
related to NOX66 use. Any signals of efficacy will be described in the Clinical Study Report and 
used to support the Phase 2/3 development program. 
12.2 STATISTICAL METHODOLOGY 
This section describes the planned statistical analyses in general terms. A complete 
description of the statistical analysis will be specified in a statistical Analysis Plan (SAP) 
finalised prior to completion of the study. 
General: Data will be summarized by using counts and percents for discrete parameters, and 
by descriptive statistics (e.g. number of observations, mean, standard deviation, median, 
minimum and maximum) for continuous parameters. Subject disposition and baseline 
characteristics will be presented for all treated patients. Data will be analysed as collected. 
No imputation of values for missing data will be performed. Standard clinical monitoring and 
data management practices will be used to ensure the integrity of the data. 
Populations for analysis: There will be two study populations defined for this study. The 
safety population will consist of all patients who received at least one dose of NOX66. This 
population will be used in all safety summaries. The efficacy population will consist of all 
patients who complete radiation therapy with at least 7 days of NOX66 dosing. 
Baseline Comparisons and Patient Disposition: Demographic and baseline disease 
characteristic data summarisation will be performed in order to descriptively document any 
safety and efficacy findings. Data to be tabulated will include demographic features such as 
age and race, as well as medical history. The number and percentage of patients who 
complete the study or who withdraw for any reason will be presented. 
Efficacy Analysis: Results from (i) RECIST 1.1 response assessment for target lesions and non-
target lesions, (ii) ECOG Performance Score and (iii) Pain scores. Changes form baseline in 
levels of serum PSA levels will be listed. 
Overall and progression-free survival, PSA and pain scores collected during the extended 
follow-up period will be summarized in the same manner as for the immediate post-
treatment follow-up period. 
Safety Analysis: The safety will be assessed through the analysis of the reported incidence of 
treatment emergent AEs, including SAEs, dose-limiting toxicities, AEs leading to withdrawal, 
events of at least CTCAE Version 4.03 Grade 3 in severity, and AEs related to study treatment. 
Treatment emergent AEs are those with an onset on or after the initiation of therapy. Other 
safety endpoints include laboratory results, physical examinations, vital signs, and changes in 
ECOG status. A copy of CTCAE Version 4.03 scoring system may be downloaded from:  


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http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
The adverse events will be summarized by MedDRA coding terms, System Organ Class (SOC), 
and preferred term for all treated patients and by dose cohort. The AEs will also be tabulated 
by maximum severity and maximum relationship to study drug where applicable. The number 
and percent of patients experiencing dose-limiting toxicities will be summarized by dose 
cohort, by DLT, and system organ class for all treated patients. Other safety endpoints, which 
include change from baseline in laboratory results and vital signs, and shifts in physical 
examinations, will be summarized throughout the study by visit for each dose level for all 
treated patients. 
Concomitant medications:  are to be listed for all patients. 
 
12.3 PROCEDURES FOR HANDLING MISSING, UNUSED AND SPURIOUS DATA 
No imputation of values for missing data will be performed. Standard clinical monitoring and 
data management practices will be used to ensure the integrity of the data 
Interim analysis 
Interim analyses will be conducted after last patient in dose Cohort 3 has completed 6-week 
follow up (Visit 8) and will be used to determine the progress of the study and dose decision 
for expansion Cohort 4. Further analysis will be conducted after each cohort has completed 
12 and 24 weeks follow up (Visit 8 and 10).  
 
 


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13 MONITORING 
13.1 MONITORING OF CASE REPORT FORMS 
The study will be monitored by a CRO on behalf of the Sponsor. Monitoring will be conducted 
per ICH GCP guidelines and Sponsor SOPs. The Monitor will visit the Investigator at regular 
intervals to review the progress and conduct of the study. The CRFs will be checked for 
completeness and accuracy against the patient records, charts, laboratory reports, and scans. 
Anonymity of the patient will be maintained at all times. 
13.2 SAFETY DATA MONITORING 
The Study Steering Committee (SSC) will review and evaluate all toxicities causally associated 
with NOX66 treatment and or the radiation therapy combination therapy. The SSC will consist 
of:  
• Principal Investigator from each clinical site, or medical designee 
• Sponsor’s Medical Monitor 
• CRO Medical Representative (if applicable) 
• Director of Clinical Development, Noxopharm Ltd 
Review of any adverse events of Grade 2 toxicity and above, considered by the Principal 
Investigator to be related to idronoxil (NOX66), will be reported to the SSC immediately and 
decision on the continuation of the patient individually, and the study in general, will be 
provided.  
The Study Steering Committee will review the Safety Data and determine dose cohort 
escalation following completion of treatment cycle (Visit 7) of final patient in a cohort.  
The SSC will determine the dose for cohort expansion based on the review of accumulated 
safety data, on treatment response and disease evaluation following WEEK 6 assessments of 
all patients and determine continuation of the study.  
 
13.3 AUDITING 
Regulatory authorities, the HREC/EC or the Sponsor may request access to patient clinical 
notes and other relevant study documentation for an on-site audit or inspection at any time 
during or after study completion. The Investigator is obliged to facilitate this process by 
allowing full access. 
 
 


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14 ADVERSE EVENTS REPORTING 
Adverse events (AE) or serious adverse events (SAE) reported by the patient or observed by 
the Investigator will be listed individually on an adverse event form in the CRF. The signs and 
symptoms, time of onset, duration, treatment (if any), and follow-up procedures (if any) will 
be reported, and the criteria for assessing causality to study drug and outcome categories 
should be defined. 
Pre-existing conditions or illnesses which are expected to exacerbate or worsen are not 
considered adverse events and will be accounted for in the patient’s medical history. 
All adverse events are to be followed up for 30 days following the end of study or until 
resolution (whichever is sooner).  
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
14.1 DEFINITIONS 
14.1.1 AE 
AE is any un-anticipated or unintended medical occurrence or worsening of a sign or symptom 
(including an abnormal laboratory finding) or disease in a study participant, which does not 
necessarily have a causal relationship with the study condition, procedures or study agent(s) 
that occurs after the informed consent is obtained. 
14.1.2 SAE 
An SAE is defined as any untoward medical occurrence that results in death, is immediately 
life-threatening, requires at least a 24-hour in-patient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect. 
The definition of SAE also includes any important medical event. Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the previous definition. These should also 
usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
Progression of malignancy (including fatal outcomes), if documented by the use of an 
appropriate method (for example, as per RECIST 1.1 criteria for solid tumours), should not be 
reported as an SAE and must be approved by the Sponsor. 


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Treatment within or admission to the following facilities does not meet the criteria of “in-
patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room  
• Outpatient or same-day surgery units 
• Observation or short-stay unit  
• Rehabilitation facility  
• Hospice or skilled nursing facility  
• Nursing homes, custodial care or respite care facility  
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which 
was planned prior to entry in the trial), does not require reporting as a SAE to the Medical 
Monitor and Sponsor. 
The definition of “related” is that there is a reasonable possibility that the drug caused any of 
the adverse events described in Table 2. 
14.1.3 Guidelines for determining causality and severity 
The criteria used for determining the relationship between the study drug/s and the Adverse 
Event are shown in Tables 2 and 3: 
Table 2 Criteria for determining relationship between AE and idronoxil (NOX66) 
Unlikely/unrelated: 
An AE with a temporal relationship to drug administration, which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations.  
Possible 
An AE with a reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear. 
Likely 
An AE with a reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (rechallenge). Rechallenge 
information is not required to fulfil this definition 
Certain 
An AE occurring in a plausible time relationship to drug administration and cannot 
be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drugs should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically using a satisfactory 
rechallenge procedure if necessary and feasible 
 
 
 


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Table 3. Adverse event outcome categories 
Resolved’  
The patient has fully recovered from the adverse event with no residual 
effects observable. 
‘Resolved with Sequelae’  
The patient has recovered from the adverse event, however there are 
residual effects observable. 
‘Ongoing’  
The adverse event is still present and observable.  
 ‘Death”  
The patient died as a result of the adverse event.  
‘Unknown’  
The outcome of the adverse is unknown at the time of report. 
 
14.2 RESPONSIBILITIES FOR REPORTING 
Investigators and the Sponsor are required by regulatory agencies worldwide to report 
adverse events which involve patients being administered a pharmaceutical product.  
All serious adverse events (SAE) occurring from the signing of informed consent until 30 
calendar days after last study visit whether related to drug or not, must be reported to the 
Medical Monitor and appropriate Sponsor contact person within 24 hours of first knowledge 
of the experience using the appropriate study SAE Report Form. SAEs are to be followed until 
resolution or stabilisation (with autopsy report if applicable). 
Although pregnancy is not a formal SAE, if the study participant or the partner of a study 
participant becomes pregnant while the study participant is on study, the pregnancy is to be 
reported on the pregnancy report form via the SAE process. 
Deaths and other SAEs occurring > 30 calendar days after last study visit that are deemed 
‘possibly’ or ‘probably’ related to the study treatment must be reported as SAEs on the SAE 
Report Form within 1 day of first knowledge of the event by the treating physician or research 
personnel (with an autopsy report if available). 
Deaths occurring > 30 calendar days after last study visit and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on 
the appropriate CRF. 
The investigative sites will send the SAE report to the Sponsor’s Medical Monitor via fax or e-
mail and to the Sponsor’s pharmacovigilance manager using the contact information below.  
 
 


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Primary Contact 
Professor Paul de Souza 
Tel: +61 404 003 220       
Email:  P.DeSouza@westernsydney.edu.au          
Alternate Contact   
Study Manager: Marinella Messina 
Tel: + 61 2 9144 223; Fax: + 61 2 9199 9600   
Email:  marinella.messina@noxopharm.com         
Pharmacovigilance 
 (DATAPHARM Australia) 
Manager: Hong-Van Dang-Beck 
 
Tel #: 61 2 9719 2800; Fax #: 61 2 9719 2811 
Email: hongvan.dangbeck@datapharmaustralia.com 
 
Transmission of the SAE Report Form should be confirmed by the site personnel submitting 
the report. The first report must contain as minimum the study ID, patient number, a description 
of the event, the name of the investigational product, estimate of causality and the name of the 
person reporting the event. 
14.2.1 SAE and Unresolved AE Follow-Up 
Follow-up information for SAEs and information on non-serious AEs that become serious 
should also be reported to the Medical Monitor as soon as possible using the SAE Report 
Form.  
The patient should be followed until it is determined that the event resolved, stabilized, or in 
the opinion of the Investigator the event is not going to improve due to underlying disease, 
or the patient is lost to follow-up. 
Investigators must report SAEs and follow-up information to their responsible HREC according 
to the policies of the responsible HREC. 
The detailed SAE reporting process will be provided to the sites in the SAE reporting guidelines 
contained in the study reference manual. 
14.2.2 Investigator Reporting of AEs/SAEs/Deaths after Study Discontinuation 
Thirty days after completing protocol-specific treatment or study discontinuation, treatment 
related AEs, SAEs, or deaths determined by the Investigator as treatment related are to be 
reported directly to the Sponsor. 
At the last scheduled study visit, the Investigator should instruct the patient to report to the 
Investigator any subsequent SAEs that the patient or the patient’s personal physician believes 
could be related to prior study treatment. 
SAEs after study discontinuation considered related to study treatment are to be sent to the 
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14.2.3 Sponsor SAE Reporting Requirements 
The Sponsor is responsible for reporting relevant SAEs/Suspected Unexpected Serious Adverse 
Reactions (SUSARs) to the competent authority, regulatory authorities (e.g. TGA), and 
participating investigators, in accordance with International Council on Harmonization (ICH) 
guidelines and/or local regulatory requirements. 
The Sponsor is responsible for reporting unexpected fatal or life-threatening events 
associated with the use of the trial drugs to the regulatory agencies and competent 
authorities via telephone or fax within 7 calendar days after being first notified of the event. 
The Sponsor will report all related but unexpected SAEs including non-death/non-life-
threatening related but unexpected SAEs associated with the use of the trial medications to 
the appropriate competent authorities (according to local guidelines), investigators, and 
relevant HREC by a written safety report within 15 calendar days of notification. 
 
 
 
 


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15 CONDUCT OF STUDY 
15.1 HUMAN RESEARCH 
The Protocol and all other relevant study documents (informed consent, advertising etc) will 
be submitted to the site Human Ethics Review Committee (HREC) and to regulatory 
authorities in the countries where the study will be conducted.  
Written confirmation of approval (noting version/ date of all approved documents) must be 
received the Investigator before the study commences and approval of all documents 
pertaining to this study will be kept in the study Master file. 
The HREC will have at all times the right to review all source documentation. 
 
15.2 GOOD CLINICAL PRACTICE 
The study will be conducted in accordance with the principles of good clinical practice (GCP) 
using the guidelines established in 1996 by the International Council on Harmonisation (ICH), 
annotated in July 2000 by the TGA.  
Compliance with these guidelines ensures compliance with the currently approved version of 
the Declaration of Helsinki (October 2000) with notes of Clarification in 2002 (Washington) 
and 2004 (Tokyo) and any local legal and regulatory requirements. 
 
15.3 ADHERENCE TO PROTOCOL 
No changes or deviations in the conduct of this protocol will be permitted, with the exception 
of emergency situations. The Investigator should contact the Sponsor by telephone as soon 
as possible. The nature and reasons for the protocol deviation should be recorded in the CRF.  
In the event of an emergency, the Principal Investigators will institute any medical procedures 
deemed appropriate. However, all such procedures must be promptly reported to the 
Sponsor, the Medical Monitor, and the HREC. 
Protocol violations are defined as any deviation from this protocol, and include items such as 
a study required evaluation not completed according to the protocol, a study visit completed 
outside of the defined visit window, etc.  
A major protocol violation would include, but not be limited to, the following: 
• enrolment of a patient who does not meet the inclusion/exclusion criteria.  
• enrolment of a patient who has not provided informed consent  
• the non-reporting of serious adverse events according to protocol and regulatory 
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All protocol violations will be reported to the Sponsor via a protocol violation form. Major 
protocol violations must be reported to the Sponsor as soon as the Investigator or the Data 
Monitor becomes aware of them. 
All major protocol violations will be reported to the Human Research Ethics Committee 
(HREC) with response and approval required for any change or deviation that may increase 
risk to the Patient, and/or that may adversely affect the rights of the Patient or validity of the 
investigation.  
 
15.4 PROTOCOL AMENDMENTS 
Amendments to the protocol need to be approved by the Sponsor and the Study Steering 
Committee. Major amendments will require the approval of the HREC. Minor amendments 
will require that the HREC be notified. Any amendments affecting the involvement of patients 
would require all patients being notified. 
 
 


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16 PATIENT INFORMED CONSENT 
The patient informed consent form contains the 20 elements required for the provision of 
informed consent as described in ICH E6(R2) 4.8. in accordance with the Code of Federal 
Regulations (21 CFR 50.25) and the latest amendment of the Declaration of Helsinki (October 
2013). Additionally, the informed consent form has been reviewed and approved by the 
Sponsor and the study HREC prior to initiation of the study. 
The Principal Investigator, or a person designated by the investigator, is responsible to explain 
the nature of the study and the risks and benefits of taking part to the patient in order to 
obtain the patent's written consent. It should be stressed that participation is voluntary. The 
patient can refuse to participate and is free to withdraw from the study at any time, without 
affecting their future medical management.  
Prior to undertaking any study specific activity, the Investigator should explain the nature of 
the study to the patient, including providing a written information sheet which should be read 
and retained by the patient. All patients must give fully informed consent, which must be 
obtained in writing by a personally dated signature and witnessed. The signed consent form 
should be available to be viewed by the Clinical Study Monitor and a copy of all consent 
documents provided to the patient. 
Patients must be informed that representatives of the Sponsor, HREC and regulatory 
authorities may inspect their medical records in order to verify the accuracy and authenticity 
of study documentation including information entered in the eCRF. Patients must be 
informed as to the nature of the privacy guidelines in place to protect their anonymity. 
Any amendments to the Informed Consent Form will need to be approved by the Sponsor and 
the HREC. 
17 DISCLOSURE OF DATA 
17.1 CONFIDENTIAL INFORMATION 
Patient medical information obtained during the study is confidential and disclosure to third 
parties other than those noted below is prohibited. All patients will be assigned a study 
identification number.  
Patients will be identified on case report forms only by their patient number and initials. 
At the patient’s request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection on request by representatives 
of state and federal health authorities, the Sponsor, and the HREC. 
All published information from this study will be presented in such a way that it does not 
permit identification of individual patients. Patient identity will remain protected except as 
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To fully evaluate patient safety issues that may arise during the study, Sponsor, or state and 
federal authorities will require direct access to source documents including trial-related 
monitoring, audits, HREC review and regulatory inspection(s). 
It must be explained to the patient before enrolment into the study that the patient’s 
Protected Health Information (PHI) obtained during the study may be shared with the study, 
Sponsor, state and federal authorities, and HREC regulatory inspections(s). 
17.1.1 Study records and source documents 
All clinical information obtained by the Investigator is confidential, including that supplied by 
the Sponsor, and disclosure to third parties must be limited to: 
i. 
Those undertaking legitimate peer review of the scientific and ethical aspects of the 
study such as, but not limited to, the TGA and/or FDA. 
ii. 
Other staff participating in the study, so that necessary medical care can be 
undertaken. 
iii. 
The patients, so that written informed consent can be obtained. 
iv. 
Representatives of the sponsor, including the Monitor(s). 
Patients will be identified to the sponsor and regulatory authorities only by their study 
number and initials recorded on the CRF. Other patient details are to be obscured if a 
document is being forwarded to the Sponsor with the CRF or provided to regulatory 
authorities for review. 
The Investigator will maintain a patient screening and enrolment log (patient numbers and 
the corresponding patient names) to enable the records to be identified. 
17.1.2  Prior to study commencement 
Prior to the release of clinical study supplies and the study commences, the following 
documents will be collected from the Principal Investigator: 
i. An up-to-date, signed and dated Curriculum Vitae for all Investigators and other study 
staff. 
ii. The signed Protocol and any amendments. 
iii. The signed clinical study agreement (CSA). 
iv. The signed letter from the HREC giving approval for the study (version numbers/dates 
of all approved documents to be included), together with a letter of constitution of 
the HREC. Copies of any other correspondence with the HREC relevant to the study 
should also be supplied. 
v. The signed letter from the relevant national authority acknowledging the study. 
vi. Current laboratory certification of the laboratory(ies) performing analysis, as well as 
current normal laboratory ranges for all laboratory tests. 
The Investigator shall provide to the Sponsor all observations and test results required in the 
protocol and indicated in the CRFs. In particular, all details of adverse events, as defined in 
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17.1.3 Document retention 
The Principal Investigator will retain copies of the following documents in a secure place for 
a period of 15 years from completion of the study per Therapeutic Goods Administration 
(TGA). These documents may be retained for a longer period by agreement with the Sponsor. 
i. A signed copy of the Protocol and any amendments. 
ii. Copies of the patients' Case Report Forms and Data Clarification Forms. 
iii. The patient informed consent documents. 
iv. Copies of the Curricula Vitae of the Investigator and study staff. 
v. Copies of all correspondence with the HREC and national regulatory authority. 
vi. Copies of relevant laboratory ranges. 
vii. Copies of all correspondence to and from the Sponsor and the Monitor and the 
Investigator. 
viii. The patient's original clinical notes. 
The Sponsor will provide the Principal Investigator with information concerning the current 
status of the investigational drug as it relates to the Investigator’s obligation for the retention 
of study records.  
The Investigators should contact the Sponsor prior to disposing of any such records. The 
Sponsor will arrange for continued storage of all records, if necessary and as documented in 
the Clinical Study Agreement. 
The Sponsor will maintain correspondence with the Principal investigator after study closeout 
to ensure that study documentation is retained for the appropriate amount of time. The 
investigator must inform the Sponsor immediately if any documents are to be destroyed, to 
be transferred to a different facility, or to be transferred to a different owner. 
In the event the investigator withdraws from the study (e.g., relocation, retirement), the 
records shall be transferred to a mutually agreed-upon designee (e.g., another investigator). 
Notice of such transfer will be given in writing to the Sponsor. 
17.1.4  Access to source documents 
To ensure the accuracy of the data collected in the CRFs, representatives from the Sponsor, 
Regulatory Authorities and the Monitor may require access to source documents (i.e. patient 
records, patient charts, laboratory reports, X-ray reports and scans). Anonymity of the patient 
will be maintained at all times. 
17.1.5 Publication policy 
To avoid disclosures that could jeopardize proprietary rights, Investigators are required to 
submit all publications to the Sponsor prior to submission to a publisher. The Sponsor will 
review any such submissions within 30 days of receipt. Permission to publish will not be 
withheld unreasonably. 


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Details of the study will be registered prior to commencement at www.clinicaltrials.gov, with 
information updated throughout the course of the trial. Publication in medical or scientific 
journals will conform to guidelines set out in the International Committee of Medical Journal 
Editors (ICMJE)1,and consult reporting standards such as the CONSORT2 group and the 
individual journals. 
Available on http://www.icmje.org and on http://www.consort-statement.org  
 
18 ADDITIONAL PATIENT CARE DURING POST-STUDY 
18.1 EMERGENCY CONTACT 
18.1.1 Investigator 
The Principal Investigator, or nominated deputy, will be available for consultation by the 
patient at any time during the study period. Names and telephone numbers of staff 
responsible for the study will be made available to the patient. The Investigator must ensure 
that adequate medical care is provided for any adverse events. The Investigator should inform 
the patient when medical care is required for any intercurrent illness. 
18.1.2 Sponsor 
In an emergency, the Principal Investigator should contact both the study Sponsor and the 
Monitor by telephone. 
18.1.3 Liability and Insurance 
With effect from the commencement of the study, the Sponsor will indemnify study 
participants according to the local institutional regulations concerning clinical study 
involvement. 
 
 


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4. Szakacs G, Paterson J, Ludwig JA, et al. (2006). Targeting multidrug resistance in cancer. 
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5. Willers H, Azzoli CG, Santivasi WL, Xia F. (2013). Basic mechanisms of therapeutic 
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6. Bussink J, van der Kogel AJ, Kaanders JH. (2008). Activation of the PI3-K/AKT pathway and 
implications for radio-resistance mechanisms in head and neck cancer. Lancet Oncol 
9:288-296. 
7. Toulany M, Kehlbach R, Florczak U, et al. (2008). Targeting of AKT1 enhances radiation 
toxicity of human tumour cells by inhibiting DNA-PKcs-dependent DNA double-strand 
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35. Formenti SC, Demaria S. 2013. Combining radiotherapy and cancer immunotherapy: a 
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20 APPENICIES 
20.1 APPENIDIX 1- ECOG SCORE* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity and Response Criteria Of The Eastern Cooperative Oncology Group. Am. J. Clin. 
Oncol. 5:649-655, 1982. Eastern Cooperative Oncology Group, Robert Comis, M.D., Group Chair. 
 
 


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20.2 APPENDIX 2- BPI-SF 
Sample of Brief Pain Inventory Short Form Questionnaire 
 
 
 


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