Phase Ia/Ib and Potential Phase IIa Study of the Safety and Pharmacokinetics of NOX66 Both as a Monotherapy and in Combination With Carboplatin in Patients With Refractory Solid Tumours
Phase: PHASE1
Conditions: Cancer
Sponsor: Noxopharm Limited

 
 
2019 
NOX66-001A                       
Protocol Version 3.0 
NCT02941523 
NOXOPHARM LIMITED 

NOXOPHARM Ltd. 
 
CONFIDENTIAL 
 
 
 
CLINICAL PROTOCOL 
 
Title: 
Phase Ia/Ib and Potential Phase IIa Study of the Safety and 
Pharmacokinetics of NOX66 Both as a Monotherapy and in Combination 
with Carboplatin in Patients with Refractory Solid Tumours 
 
Protocol Number: 
NOX66-001A 
 
Product: 
 
NOX66 (Idronoxil Suppository Formulation) 
 
Sponsor: 
Noxopharm Limited 
50 Queen Street, Melbourne,  
Victoria, 3000, Australia 
Telephone: 61 2 9144 2223 
Mobile:  61 429 854 390 
 
Version: 
 
 
3.0 
 
Date:  
 
 
20th  July 2017 
  
 
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 subject 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’. 

NOXOPHARM Ltd. 
 
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INVESTIGATOR SIGNATURE  
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. 
 
PRINCIPAL INVESTIGATOR 
 
 
 
 
 
 
 
Name 
 
Signature 
 
Date 
 
 
 

NOXOPHARM Ltd. 
 
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1 STUDY SYNOPSIS 
Name of Company Sponsor 
NOXOPHARM LIMITED 
Title of Study 
Phase Ia/Ib and Potential Phase IIa Study of the Safety and Pharmacokinetics of 
NOX66 Both as a Monotherapy and in Combination with Carboplatin in Patients 
with Refractory Solid Tumours 
Study Number 
NOX66-001A 
Development Phase 
Phase 1a/1b  
Name of Active Ingredient  
Idronoxil 
Description of 
Investigational Product 
NOX66 is idronoxil formulated as a suppository in a standard suppository base. 
Each suppository contains 400 mg idronoxil. 
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 either 400 mg daily (1 suppository daily) or 800 mg daily (1 suppository 
twice daily).  
Number 
of 
Subjects 
(planned) 
For the Phase Ia and Ib arms of the Study a total of 16 (evaluable) patients will be 
recruited and divided into 2 Cohorts of 8 patients each as follows: 
Cohort 1: 400 mg idronoxil dosage. 
Cohort 2: 800 mg idronoxil dosage. 
The maximum number of patients to be recruited in Phase I arms is 22 patients. 
The Phase IIa arm is triggered by an objective response to combination therapy 
in the Phase Ib arm. For this, 10-12 additional subjects with the same tumour type 
will be enrolled on the same combination treatment regimen. There will be a 
maximum number of two (2) such Phase IIa cohorts, each with a maximum of 24 
subjects. 
If Phase IIa proceeds with 2 further cohorts (Cohorts 3 and 4), the total number 
of patients enrolled in the Study will be 34 -40. 
Indication 
Solid tumours with no standard therapeutic alternatives. 
Study Period and Duration 
of Treatment 
Treatment in the Phase Ia (Run-In) Arm is for 1 Treatment Cycle (14-days 
treatment followed by 1 week of rest) only.  
Treatment in the Phase Ib (Combination) Arm is intended to be for a maximum of 
6x 28-day Treatment Cycles (total treatment time = 6 months). However, 

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combination treatment cycle may continue if the Investigator considers that there 
is clinical benefit to the subject, and that the benefits outweigh the risks. 
Treatment in Phase IIa (Combination) Arm is intended to be for a maximum of 6x 
28-day Treatment Cycles (total treatment time = 6 months). 
Primary Study Objective 
• to determine the tolerability, adverse event profile, maximum tolerated dose 
(MTD), and dose-limiting toxicities (DLTs) of idronoxil in a suppository dosage 
form (NOX66) in patients with refractory solid tumours, both as a single agent 
and in combination with carboplatin 
• to determine if idronoxil in a suppository dosage form (NOX66) is able to 
combine with a standard dosage of carboplatin to produce a meaningful anti-
cancer effect in solid tumours considered to be refractory to cytotoxic 
chemotherapy 
• to determine if idronoxil in a suppository dosage form (NOX66) is able to 
combine with dosage of carboplatin two-thirds of the standard dosage to 
produce a meaningful anti-cancer effect in solid tumours considered to be 
refractory to cytotoxic chemotherapy 
Secondary Study Objectives 
• to characterise some key pharmacokinetic features of idronoxil when 
administered rectally 
• to determine if various biomarkers of idronoxil biologic activity have any 
correlation to the efficacy or toxicity of idronoxil in combination with 
carboplatin. 
Methodology 
The Study has 3 separate components - Phase Ia, Phase Ib and a potential Phase 
IIa component. 
The Phase 1a component will comprise 21-day Run-In Arm of idronoxil 
monotherapy administered on a two-step dose-escalation basis. Patients to 
receive idronoxil treatment once or twice (12-hourly) daily for 1 Treatment Cycle 
only.  
Cohort 1: 
400 mg idronoxil daily. 
Cohort 2: 
800 mg idronoxil daily. 
In each regimen, treatment is taken daily for 14 consecutive days followed by 7 
days of rest, comprising a 21-day Treatment Cycle. 
Any patient experiencing Dose-Limiting Toxicity (DLT) in Cohort 1 will have their 
dosage halved to 400 mg idronoxil every 2nd day. 
Any patient experiencing DLT in Cohort 2 will revert to Cohort 1 treatment 
regimen. 
The Phase Ib component will comprise idronoxil administered in combination 
with carboplatin up to 6 Treatment Cycles each of 28-days. 
All patients completing the Run-In Arm without significant toxicity will be offered 
combination treatment with carboplatin. Patients will remain in the same Cohort 

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(1 or 2) and be treated with idronoxil at the same dosage received in the Run-In 
Arm and receive the following treatment with carboplatin. 
Carboplatin Regimen 1: carboplatin AUC = 4 for Treatment Cycles 1-3 
Carboplatin Regimen 2: carboplatin AUC = 6 for Treatment Cycles 4-6. 
Idronoxil to be administered Days 1-7 of each 28-day Treatment Cycle. 
Carboplatin to be given intravenously on Day 2 of each Treatment Cycle. 
Note: maximum dose for AUC = 4 is 600 mg and for AUC = 6 is 900 mg. 
DLT will be managed with a mixture of a reduction in dosage or withholding of 
idronoxil and/or carboplatin, to be determined in consultation with the 
Investigator, the Medical Monitor, and the Sponsor 
The Phase IIa component can be triggered by observed meaningful clinical 
responses from the Phase Ib Arm in particular disease indications and will be 
activated only with the agreement of the Principal Investigators. The combination 
treatment of idronoxil + carboplatin will be administered over 6 Treatment Cycles 
each of 28-days at dosages considered appropriate by mutual agreement 
between the Sponsor and the Principal Investigators. A maximum of 2 additional 
patient cohorts, each comprising an additional 10-12 patients with specific 
disease states can be enrolled. 
Criteria for Evaluation 
Safety: to be assessed through the analysis of routine laboratory tests 
(haematology, serum chemistry, urinalysis), physical examinations, vital signs, 
and ECOG status. Adverse event monitoring will be performed and assessed using 
the CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.03 (CTCAE) scoring system.  
Efficacy: All efficacy assessments will be performed at the discretion of the 
Investigator but at a minimum should include a baseline assessment (CT scan, 
ECOG assessment) and follow-up assessments at a minimum of every 12 weeks 
while receiving study drug. Tumor response and progression-free survival will be 
assessed using standard RECIST criteria. 
Pharmacokinetics:  blood and 24 hour-urine samples will be analysed to 
determine the primary idronoxil metabolites and the primary route of excretion. 
Biomarkers: Ceramide and sphingosine-1-phosphate (related to the molecular 
target of idronoxil) and ENOX2 will be assessed at baseline and at completion of 
idronoxil therapy per cycle. Biomarker and plasma idronoxil levels to be 
correlated with anti-cancer activity and any toxicity. 
Statistical Methods 
Statistical analyses will be primarily descriptive in nature and statistical 
hypothesis testing will not be performed. All patients will be included in the 
evaluation of safety. Data will be presented by Cohort, by idronoxil and 
carboplatin dosages, and by tumour type. 
Inclusion Criteria 
1. Provision of informed consent. 
2. Male or female ≥18 years of age. 

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3. Histologic or cytologic confirmed locally advanced or metastatic cancer that 
has no standard therapeutic alternatives. 
4. At least 1 measurable lesion by CT/MRI scan. 
5. ECOG Performance status 0-1 (Appendix A). 
6. A minimum life expectancy of 12 weeks. 
7. 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  
8.  Female patients who are known to be capable of conception should have a 
negative serum pregnancy test (beta-human chorionic gonadotropin (β-
hCG)) within 1 week of starting the study. 
9. All potentially fertile patients will agree to use an effective form of 
contraception during the study and for 90 days following the last dose of 
NOX66 (an effective form of contraception is defined as an oral contraceptive 
or a double barrier method. 
10. 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 Grade 1. 
11. At least 21 days must have elapsed prior to Day 1 Cycle 1 since radiotherapy 
(limited palliative radiation is allowed > 2 weeks), immunotherapy or 
following major surgery and any surgical incision should be completely 
healed. 
Exclusion Criteria 
1. Patients who are pregnant or breastfeeding.  
2. Tumor involvement of the Central Nervous System (CNS):  
• Patients with treated and stable CNS metastases may be eligible to 
participate after discussion and approval from the Medical Monitor. 
3. Uncontrolled infection or systemic disease.  
4. 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.  
5. Patients with QTc of > 470 msec on screening ECG. (If a patient has QTc 
interval >470 msec on screening ECG, the screening ECG may be repeated 
twice (at least 24 hours apart). The average QTc from the 3 screening ECGs 
must be <470 msec in order for the patient to be eligible for the study.  
6. Any major surgery, radiotherapy, or immunotherapy within the last 21 days 
(limited palliative radiation is allowed > 2 weeks).  

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7. Chemotherapy regimens with delayed toxicity within the last 4 weeks. 
Chemotherapy regimens given continuously or on a weekly basis with limited 
potential or delayed toxicity within the last 2 weeks.  
8. Any situation where the use of suppository therapy is contra-indicated or 
impractical (e.g. chronic diarrhea, colostomy, ulcerative colitis). 
9. No concurrent systemic chemotherapy or biologic therapy is allowed.  
10. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, 
previously treated or both).  
11. History of solid organ transplantation.  
12. Psychiatric disorder or social or geographic situation that would preclude 
study participation.  
13. Known unsuitability for treatment with carboplatin including renal disease 
where there is impaired glomerular filtration rate (GFR). 
 

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2 LIST OF TABLES 
Table 1. Number of Boxes of NOX66 to be Dispensed per Treatment Regimen.......................... 32 
Table 2. NOX66/Idronoxil Dose Level Schema.............................................................................. 34 
Table 3. Dose escalation Decision Rules for Run-In Arm .............................................................. 35 
Table 4. Schedule of Assessments – SCREENING .......................................................................... 41 
Table 5.  Schedule of Assessments -Phase Ia (Run-In) Arm .......................................................... 41 
Table 6. Schedule of Assessments -Phase Ib (Combination) Arm ................................................ 42 
Table 7. Schedule of NOX66 Treatment in Phase Ia (Run-In) Arm ............................................... 42 
Table 8. Schedule of NOX66 Treatment in Phase Ib (Combination) Arm per Cycle ..................... 42 
Table 9. Schedule of Assessments - Phase IIa Arm ....................................................................... 43 
Table 10. PK Blood Sampling Schedule for Phase Ia (Run-In) Arm ............................................... 44 
Table 11. Biomarker Blood Sampling Schedule for Phase Ia (Run-In) Arm .................................. 44 
Table 13: Adverse Event Outcome Category ................................................................................ 55 
 
 
 

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3 LIST OF ABREVIATIONS 
Abbreviation/term 
Definition 
AE 
Adverse Event 
0C 
Degrees Celsius 
CBC 
Complete Blood Count (otherwise known as FBC) 
CFR 
Code Federal Regulations 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CT 
Computerised Tomography 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ENOX2 
Tumour-associated NADH oxidase 
FDA 
Food and Drug Administration 
G 
Gram(s) 
GCP 
Good Clinical Practice 
Hr 
Hour 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
Kg 
Kilogram 
M 
Micro 
mM 
Micromolar 
Mg 
Milligram(s) 
mL 
Milliliter(s) 
Min 
Minute(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI CTC 
National Cancer Institute, Common Toxicity Criteria 
PFS 
Progression Free Survival 
PR 
Partial Response 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 

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TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ..................................................................................................................... 4 
2 
LIST OF TABLES ........................................................................................................................ 9 
3 
LIST OF ABREVIATIONS.......................................................................................................... 10 
4 
ROLES AND RESPONSIBILITIES .............................................................................................. 16 
4.1 
SPONSOR ........................................................................................................................ 16 
4.2 
INVESTIGATOR AND SITES .............................................................................................. 16 
4.3 
CLINICAL RESEARCH ORGANISATION ............................................................................. 17 
5 
INTRODUCTION ..................................................................................................................... 18 
5.1 
OVERALL AIM ................................................................................................................. 18 
5.2 
BACKGROUND ................................................................................................................ 18 
5.2.1 
General .................................................................................................................... 18 
5.2.2 
Regulatory Background of Idronoxil ....................................................................... 19 
5.3 
CLINICAL EXPERIENCE ..................................................................................................... 20 
5.4 
RATIONALE FOR NOX66 ................................................................................................. 21 
5.5 
SUPPOSITORIES – STANDARD THERAPY......................................................................... 22 
5.6 
POTENTIAL RISKS ............................................................................................................ 22 
6 
STUDY OBJECTIVES ................................................................................................................ 24 
6.1 
PRIMARY OBJECTIVES ..................................................................................................... 24 
6.2 
SECONDARY OBJECTIVES ................................................................................................ 24 
7 
STUDY DESIGN ...................................................................................................................... 25 
7.1 
Phase I Arm .................................................................................................................... 25 
7.2 
Phase II Arm ................................................................................................................... 26 
8 
STUDY PARTICIPANTS ........................................................................................................... 27 
8.1 
STUDY POPULATION ....................................................................................................... 27 
8.2 
INCLUSION CRITERIA ...................................................................................................... 27 
8.3 
EXCLUSION CRITERIA ...................................................................................................... 28 
8.4 
STUDY WITHDRAWRAL .................................................................................................. 29 

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8.5 
PATIENT REPLACEMENT ................................................................................................. 29 
9 
STUDY MATERIALS ................................................................................................................ 30 
9.1 
INVESTIGATIONAL STUDY PRODUCT .............................................................................. 30 
9.1.1 
Description and Formulation .................................................................................. 30 
9.1.2 
Presentation, Storage and Handling ....................................................................... 30 
9.1.3 
Labelling .................................................................................................................. 31 
9.1.4 
Procurement and Distribution ................................................................................ 31 
9.2 
INVESTIGATIONAL PRODUCT ADMINISTRATION ........................................................... 32 
9.3 
DURATION OF STUDY TREATMENT ................................................................................ 32 
9.4 
TREATMENT DOSE MODIFICATIONS .............................................................................. 32 
9.5 
ACCOUNATBILITY FOR CLINICAL SUPPLIES..................................................................... 33 
9.6 
CONCOMITANT MEDICATION ........................................................................................ 33 
10 STUDY PROCEDURES AND VISITS SCHEDULE ........................................................................ 34 
10.1 
STUDY ARMS ............................................................................................................... 34 
10.1.1 Phase Ia (Run-in) Arm ............................................................................................. 34 
10.1.2 Phase Ib (Combination) Arm ................................................................................... 35 
10.1.3 Phase IIa Arm .......................................................................................................... 36 
10.1.4 Definition and Determination of Dose Limiting Toxicity (DLT) and Maximum 
Tolerated Dose (MTD). .......................................................................................................... 37 
10.2 
CLINICAL AND LABORATORY ASSESSMENTS .............................................................. 38 
10.2.1 Demographic and Other ......................................................................................... 38 
10.2.2 Safety ...................................................................................................................... 38 
10.2.3 Pharmacokinetic and Biomarker ............................................................................ 39 
10.3 
ASSESSMENT OF DISEASE STATUS .............................................................................. 39 
10.3.1 Radiologic Assessments .......................................................................................... 39 
10.3.2 Assessment of Response in Patients with Measurable Disease ............................. 39 
10.4 
STUDY VISITS ............................................................................................................... 40 
10.4.1 Screening ................................................................................................................. 40 

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10.4.2 Phase Ia (Run-In) Arm Schedule of Procedures ...................................................... 41 
10.4.3 Phase Ib (Combination) Arm and End of Study Schedule of Procedures ............... 42 
10.4.4 NOX66 Dosing Schedules ........................................................................................ 42 
10.4.5 Phase IIa Arm Schedule of Procedures ................................................................... 43 
10.4.6 Pharmacokinetic Analysis ....................................................................................... 44 
10.4.7 Biomarker Analysis .................................................................................................. 44 
11 METHODS OF ASSIGNMENT OF INTERVENTION................................................................... 45 
11.1 
ALLOCATION OF TREATMENT ..................................................................................... 45 
11.2 
BLINDING AND UNBLINDING ...................................................................................... 45 
12 DATA COLLECTION AND MANAGEMENT .............................................................................. 46 
12.1 
METHODS ................................................................................................................... 46 
12.1.1 Case Report Form ................................................................................................... 46 
12.1.2 Return and Storage of Forms .................................................................................. 46 
12.2 
DATA MANAGEMENT ................................................................................................. 46 
12.2.1 Data Coding ............................................................................................................. 46 
12.2.2 Data Validation ....................................................................................................... 47 
13 STATISTICAL SECTION............................................................................................................ 48 
13.1 
SAMPLE SIZE ............................................................................................................... 48 
13.2 
STATISTICAL METHODOLOGY ..................................................................................... 48 
13.3 
PROCEDURES FOR HANDLING MISSING, UNUSED AND SPURIOUS DATA ................. 51 
13.4 
INTERIM AND ADDITIONAL ANALYSIS ........................................................................ 51 
14 MONITORING ........................................................................................................................ 52 
14.1 
MONITORING OF CASE REPORT FORMS .................................................................... 52 
14.2 
SAFETY DATA MONITORING ....................................................................................... 52 
14.3 
AUDITING .................................................................................................................... 52 
15 ADVERSE EVENT REPORTING ................................................................................................ 53 
15.1 
DEFINITIONS ............................................................................................................... 53 
15.1.1 AE ............................................................................................................................ 53 

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15.1.2 SAE .......................................................................................................................... 53 
15.1.3 Guidelines for Determining Causality and Severity ................................................ 54 
15.2 
RESPONSIBILITIES FOR REPORTING ............................................................................ 55 
15.2.1 SAE and Unresolved AE Follow-Up ......................................................................... 56 
15.2.2 Investigator Reporting of AEs/SAEs/Deaths after Study Discontinuation .............. 56 
15.2.3 Sponsor SAE Reporting Requirements .................................................................... 56 
15.2.4 Pregnancy ................................................................................................................ 57 
16 CONDUCT OF STUDY ............................................................................................................. 58 
16.1 
HUMAN RESEARCH ..................................................................................................... 58 
16.2 
GOOD CLINICAL PRACTICE .......................................................................................... 58 
16.3 
ADHERENCE TO PROTOCOL ........................................................................................ 58 
16.3.1 Protocol Violation and Reporting ........................................................................... 58 
16.4 
PROTOCOL AMENDMENTS ......................................................................................... 59 
17 PATIENT INFORMED CONSENT ............................................................................................. 60 
18 DISCLOSURE OF DATA ........................................................................................................... 61 
18.1 
CONFIDENTIAL INFORMATION ................................................................................... 61 
18.1.1 Study Records and Source Documents ................................................................... 61 
18.1.2 Prior to Study Commencement .............................................................................. 62 
18.1.3 Document Retention ............................................................................................... 62 
18.1.4 Access to Source Documents .................................................................................. 63 
18.1.5 Publication Policy .................................................................................................... 63 
19 ADDITIONAL PATIENT CARE DURING POST-STUDY .............................................................. 64 
19.1 
EMERGENCY CONTACT ............................................................................................... 64 
19.1.1 Investigator ............................................................................................................. 64 
19.1.2 Sponsor ................................................................................................................... 64 
19.2 
Liability and Insurance ................................................................................................ 64 
20 APPENDICIES ......................................................................................................................... 65 
20.1 
APPENDIX A  .............................................................................................................. 65 

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20.1.1 ECOG Performance Status* .................................................................................... 65 
20.2 
APPENDIX B ................................................................................................................. 65 
20.2.1 Procedure for Collection of Plasma Samples .......................................................... 65 
20.2.2 Procedure for Collection of Urine Samples ............................................................ 66 
20.3 
APPENDIX C ................................................................................................................. 66 
20.3.1 References .............................................................................................................. 66 
 
 
 
 
 

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4 ROLES AND RESPONSIBILITIES 
4.1 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:  
Marinella Messina 
 
 
 
 
 
Clinical Operations Manager 
 
 
 
 
 
Telephone: +61 2 91442223 
 
 
 
 
 
Mobile:        +61 499 005 049 
 
 
 
 
 
Email: marinella.messina@noxopharm.com 
 
Noxopharm Medical Monitor: 
Associate Professor Paul de Souza 
 
 
 
 
 
Telephone: +61 2 9350 3910 
 
 
 
 
 
E-mail: P.DeSouza@westernsydney.edu.au 
 
Local Medical Monitor:  
Dr Anton Klishvn 
Mobile: +38 050 418 0168 
Email: a.klishin@clinicalaccelerator.com 
 
4.2 INVESTIGATOR AND SITES 
No. 
Principal Investigator 
Site (Name and Address) 
1. 
Dr. Lia Abshilava 
Medulla-Chemotherapy and Immunotherapy Clinic 
A.Politkovskaia street #6 
Tbilisi, Georgia 0186 
 
2. 
Dr. Mikheil Shavdia 
JSC “Neo Medi’ 
Kristine Sharashidze Street #12 
Tbilisi, Georgia 0131 
 

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4.3 CLINICAL RESEARCH ORGANISATION 
 
Local Sponsor:  
Clinical Accelerator 
First Floor  
10-12 Prospect Hill, Douglas 
Isle of Man IM, 1EJ Great Britain 
Project manager: Ms Oksana Molchanova 
 
Data Management: 
Datapharm Australia Pty Ltd 
56-56A Thompson St 
Drummoyne NSW 2057 
Project manager: Ms HongVan DangBeck 
 

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5 INTRODUCTION 
5.1 OVERALL AIM 
This study forms part of a global program aimed at developing idronoxil (in a suppository dosage 
formulation) as an adjunct therapy that will: 
• increase the efficacy of standard frontline chemotherapies and radiotherapies 
• restore sensitivity to those frontline therapies in cancers that have become refractory 
to standard therapies 
• sensitise tumour cells to standard frontline therapies to the extent that their dosages 
can be lowered to well tolerated levels. 
5.2 BACKGROUND 
5.2.1 General 
As a general statistic, the likelihood of a cancer patient surviving 10-years following diagnosis has 
doubled from 25% to 50% over the past 45 years.  However, for many forms of cancer, 5- and 10-
year survival prospects have changed little in that time, with cancers of the pancreas, lung, gall-
bladder, head & neck, stomach and brain being obvious examples. But even where patients are 
living longer, aggressive cancers that have spread beyond their original site invariably return and 
are fatal. 
Chemotherapy and radiotherapy remain the standard frontline therapies for the great majority 
of patients and for the great majority of tumour types, despite their shortcomings.  There have 
undergone undoubted refinements over the past 45 years, but their underlying function has not 
changed and their shortcomings and limitations are unchanged. More recent developments such 
as immunotherapy have failed to dislodge chemotherapy and radiotherapy from their dominant 
position. 
The failure of chemotherapy and radiotherapy to have had a bigger impact on survival prospects 
is due to 2 factors: first, their general poisoning effect which prevents them from being used at 
higher and more effective dosages; and, second, the ability of cancer cells to become resistant to 
both drugs and radiation. 
The problem of resistance has been identified as the single largest problem facing better 
management of cancer. Without this resistance, cancer cells would be killed by much lower levels 
of chemotherapy or radiotherapy. 
This is the objective of the current global NOX66 program is to use its active drug, idronoxil, to 
remove the ability of the cancer cell to resist chemotherapy and radiotherapy so that dosages of 
those therapies that currently are providing only partial killing of cancer cells, will effectively kill 
all cancer cells within the body. 

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Scientists have identified the main biochemical mechanisms within a cancer cell responsible for 
this resistance (e.g. PI3 kinase and Akt signalling pathways) and these have become an obvious 
target for drug development. However, despite considerable effort over the past decade, no drug 
has proven effective in the clinic because of the inability of the drugs developed to date to 
distinguish between cancer cells and healthy cells. Signalling pathways such as PI3 kinase and Akt 
are essential pathways responsible for the survival of all human cells. Shutting them down in 
cancer cells in order to block the cancer cell’s ability to develop resistance mechanisms, comes 
at the cost of reducing a healthy cell’s ability to survive. 
Idronoxil is the first drug that selectively inhibits PI3 kinase/Akt in cancer cells, with no known 
adverse effects on healthy cells. As a result of this, idronoxil in the laboratory (cells and animals) 
leads to a very high level of sensitisation of all forms of cancer to the killing effects of 
chemotherapy drugs allowing dosages of those drugs to be reduced >2000-times and still achieve 
100% cancer cell killing. This effect on cancer cells is achieved with no increased sensitivity to the 
same drugs in healthy cells. 
Detail of all pre-clinical studies can be found in the IB edition 2.0, section 5.0.  
5.2.2 Regulatory Background of Idronoxil 
Both oral and intravenous dosage form of idronoxil have been used in over 400 patients in 18 
clinical studies in Australia, United States, United Kingdom, Germany, Belgium and Poland 
between 1999 -2009.  
Both dosage forms have been granted Investigational New Drug (IND) status by the United States 
Food and Drug Agency (FDA). Both dosage forms also have been awarded Orphan Drug Status 
for the treatment of late-stage ovarian cancer by the FDA.  
Both oral and intravenous dosage forms have been approved by the Australian Therapeutics 
Good Agency (TGA) for use in 8 clinical trials in cancer patients. 
Hospitals that have approved the use of idronoxil in patients include: 
UK 
• Royal Marsden Hospital 
• University College London 
• Imperial College London 
Germany 
• Campus Virschow Clinic, University Hospital, Berlin 
Belgium 
• Katolieke Universiteit Leuven 

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• Antwerp University Hospital 
Poland 
• Poznan University of Medical Sciences 
• Hollycross Oncology Centre, Kielce 
USA 
• Yale-New Haven Cancer Center 
• Augusta Oncology Associates 
• Bennett Cancer Center, Stamford 
• Cleveland Clinic 
Australia 
• Mater Adult Hospital, Brisbane 
• Westmead Hospital, Sydney 
• Royal North Shore Hospital, Sydney 
• St George Hospital, Sydney 
• Royal Prince Alfred Hospital, Sydney 
• St John of God Hospital, Perth 
• Royal Women’s Hospital, Melbour 
5.3 CLINICAL EXPERIENCE 
Eighteen (18) clinical studies (Phase 1, Phase 2, Phase 3) have been conducted with the oral and 
intravenous dosage forms of idronoxil. With the exception of one Phase 2 study in patients with 
haematological cancers, all other studies have involved patients with end-stage solid cancers. 
The primary clinical indication eventually pursued was restoration of sensitivity to carboplatin in 
late-stage, platinum-refractory ovarian cancer. 
The drug has proven to be well tolerated. No bone marrow, hepatic, renal, neurological or cardiac 
toxicity has been reported or observed in over 400 patients. Fatigue is the only reported 
monotherapy toxicity at maximum Grade 2 level in <5% patients. 
No maximum tolerable dosage level has been determined in humans. The highest dosage that is 
practically able to be administered is 40 mg/kg on a repeated daily basis, and that is without any 
toxicity. 
Details of each clinical study is available in IB Edition 2.0, section 6.0 

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5.4 RATIONALE FOR NOX66 
Idronoxil has proved to be a highly effective chemo-sensitiser in the laboratory in both in vitro 
studies and in animal models of human cancers. And while evidence of that anti-cancer effect 
has been obtained in a number of Phase 2 clinical studies, this anti-cancer effect has been 
inconsistent and infrequent, falling well short of its pre-clinical promise.  
Recent studies now suggest that a previously-unknown mechanism of drug-resistance lies behind 
this disappointing clinical result, with most tumours in most patients probably possessing an 
ability to block the effect of idronoxil. 
This phenomenon involves Phase 2 metabolism. This is an important detoxification system within 
the body designed to convert water-insoluble foreign chemicals into water-soluble forms able to 
be eliminated quickly in the urine. This is a process that idronoxil shares with other drugs such as 
aspirin, paracetamol, codeine, propofol, naxolone and steroid hormones. What all these drugs 
have in common is an underlying phenolic chemistry structure, rendering them poorly soluble in 
water. 
The Phase 2 metabolism of phenolic drugs involves two steps. Step A is the attachment by certain 
enzymes (transferases) of a sugar (glucuronic acid) to the drug. This makes the drug more soluble 
in water, allowing it to be readily transported in blood and readily excreted in urine. In this form, 
however, the drug is inactive because it is too large to bind to its target. 
Activation of the drug is Step B.  This involves the removal of the sugar, a step conducted by 
another family of enzymes (glucuronidases) present inside most cells. In Step 2, the drug + sugar 
complex leaves the bloodstream and enters its target cell where the drug is separated from its 
attached sugar and now is free to bind to its target within the cell. 
Idronoxil undergoes the same process. Following oral or intravenous dosing, 100% of all idronoxil 
in the bloodstream is subject to Phase 2 metabolism. And in common with all other phenolic 
drugs, the idronoxil + sugar complex enters a cell, is released from its sugar, and it free to work.  
Recent studies, however, have revealed that while normal cells contain the necessary 
glucuronidase enzymes, the cancer cells that have been studied are lacking in this enzyme activity 
by as much as 90%. This is assumed to be just another defence mechanism of cancer cells that 
helps them avoid chemotherapy. 
This means that the great majority of idronoxil that reaches the cancer cell remains attached to 
its sugar and unable to work. 
NOX66 has been developed to lessen the ability of the body to attach glucuronic acid to idronoxil 
so that the drug remains as much as possible in a (sugarless) form that retains is anti-cancer 
activity. In this way, the drug is not required to enter the cancer cell to have its attached sugar 

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removed and therefore is unaffected by the cancer cell’s ability to develop multiple drug 
resistance mechanisms. 
The rationale is to administer idronoxil rectally. This is intended to minimise Phase 2 metabolism 
in 2 ways: 
• first, the transferase enzymes that provide frontline Phase 2 metabolism and which occur 
in the lining of the gut from the stomach down to the large bowel, are absent in the lining 
of the rectum 
• second, that venous drainage from the lower half of the rectum is via the inferior vena 
cava, thus avoiding first pass liver metabolism. 
Collectively these 2 anatomical features are intended to minimise the degree of exposure of 
idronoxil to Phase 2 metabolism. 
Studies in rats have confirmed this rationale. Delivering idronoxil rectally as NOX66 reduces the 
degree of Phase 2 metabolism of idronoxil in rats by 90% compared to oral dosing, leaving a 
significant proportion of idronoxil circulating within the bloodstream in a non-detoxified form. 
 
5.5 SUPPOSITORIES – STANDARD THERAPY 
Many drugs are given both orally and rectally. Rectal administration generally is used for 3 
reasons: 
1. Where the patient is suffering nausea or where the drug may be irritant to the stomach; 
2. Where fast action is required (absorption generally very rapid from the rectum); 
3. Where it is considered desirable to avoid Phase 2 metabolism in the liver. 
Point 3 above is part of the rationale for NOX66. Phase 2 metabolism takes place both in the 
lining of the gut and in the liver. Drugs absorbed rectally avoid first pass liver metabolism, 
substantially reducing their exposure to the liver’s detoxification enzymes. 
NOX66 consists of idronoxil contained in a standard (commercial) fatty base used in the 
manufacture of a wide range of suppositories. 
 
5.6 POTENTIAL RISKS 
No potential risks are anticipated from the use of idronoxil in this Study based on: 
• idronoxil specifically attaches to a target that is only present on tumour cells 
• laboratory studies have failed to find any toxicity of idronoxil towards normal cells 

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• animal studies with oral or intravenous dosage formulations have been unable to 
determine the maximum tolerated dose 
• in a Phase 3 clinical study when given orally on a continuous daily basis over a 21-day 
period (at a dosage more than double the highest proposed dosage in this study) in 
combination with a standard dose of carboplatin, there was no toxicity > Grade 2. 
The administration of idronoxil as NOX66 is not expected to lead to a safety profile any different 
to that of the previously-used oral dosage form. Despite the Phase 2 metabolism of orally 
administered idronoxil, the drug still was activated within normal cells. For that reason, the effect 
of idronoxil on normal cells is predicted to be exactly the same whether given orally or rectally, 
and whether subjected to complete or incomplete Phase 2 metabolism. 
It should also be noted that this is a limited, two-step dose-escalation study of 400 and 800 mg 
idronoxil daily. Patients are to be closely monitored for safety by physical exam, hematologic and 
chemistry evaluations, urinalysis, and ECG analyses. Any evidence of toxicity is expected to be 
noted early and the dosage of NOX66 adjusted if necessary. 
 
 

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6 STUDY OBJECTIVES  
6.1 PRIMARY OBJECTIVES 
• 
to determine the tolerability, adverse event profile, maximum tolerated dose (MTD), and 
dose-limiting toxicities (DLTs) of idronoxil in a suppository dosage form (NOX66) in 
patients with refractory solid tumours, both as a single agent and in combination with 
carboplatin 
• 
to determine if idronoxil in a suppository dosage form (NOX66) is able to combine with a 
standard dosage of carboplatin to produce a meaningful anti-cancer effect in solid 
tumours considered to be refractory to cytotoxic chemotherapy 
• 
to determine if idronoxil in a suppository dosage form (NOX66) is able to combine with 
dosage of carboplatin two-thirds of the standard dosage to produce a meaningful anti-
cancer effect in solid tumours considered to be refractory to cytotoxic chemotherapy. 
 
6.2 SECONDARY OBJECTIVES 
• 
to characterise some key pharmacokinetic features of idronoxil when administered 
rectally 
• 
to determine if various biomarkers of idronoxil biologic activity have any correlation to 
the efficacy or toxicity of idronoxil in combination with carboplatin. 
 
 

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7 STUDY DESIGN 
This is a Phase I, open-label, non-randomized, dose-escalation (two-step) study of experimental 
drug, idronoxil, in a suppository dosage formulation (NOX66) in patients with refractory solid 
tumours that have stopped responding to standard treatment options.  
The patients will have solid cancers selected from 5 phenotypes: prostate, breast, ovarian, lung, 
head and neck. 
The study has two confirmed arms: a Phase Ia (Run-In) Arm where idronoxil is used alone and a 
Phase Ib (Combination) Arm where idronoxil is used in combination with carboplatin. 
A Phase IIa arm is a potential third arm. This will only be triggered by clinical responses in the 
Phase Ib arm that are considered by the Investigators to be meaningful.  
Sixteen (16) patients will be recruited and 8 patients allocated to each of two cohorts – Cohort 1 
and Cohort 2. Cohort 1 will receive an idronoxil dosage of 400 mg daily; Cohort 2, 800 mg daily. 
Recruitment into Cohort 2 will not occur until at least 7/8 Cohort 1 patients have completed at 
least 1 Phase Ia Treatment Cycle without Dose-limiting Toxicity (DLT). 
 
7.1 Phase I Arm 
In the Phase Ia (Run-In) Arm, patients will self-administer idronoxil rectally either once or twice 
(12-hourly) daily for 14 consecutive days for one (21-day) Treatment Cycle using one of 2 
idronoxil dosages.  
The main purpose of the Phase Ia Arm is to confirm the tolerability of idronoxil (in the NOX66 
dosage formulation) when used as a monotherapy over an extended period of treatment (14 
consecutive days). 
The Phase Ib (Combination) Arm will commence immediately following the Phase Ia (Run-In) 
Arm and will comprise idronoxil being administered in combination with carboplatin. Patients 
will remain in the same two starting cohorts and remain on the same idronoxil dosage. 
Within each 28-day combination treatment cycle, idronoxil treatment will commence on Day 1 
and continue daily for 7 consecutive days; carboplatin will be administered intravenously on Day 
2.  
There will be two different dosages of carboplatin administered: AUC = 4 and AUC = 6. Patients 
will start with the lower dose and receive that for 3 Treatment Cycles. Providing there is no DLT, 
patients then will progress onto the higher dosage of carboplatin which they will receive for up 
to a further 3 Treatment Cycles.  

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The primary aim of this phase is to see if idronoxil can induce a meaningful clinical response 
(complete or partial remission by RECIST) in combination with carboplatin in cancers that have 
stopped responding to standard chemotherapy and generally would be considered unlikely to 
respond to further standard therapy. And then further, to see if this meaningful combination 
anti-cancer effect is possible with a dosage of carboplatin that would be regarded generally as 
being well tolerated but unlikely to deliver a significant anti-cancer effect. 
7.2 Phase II Arm 
The Phase IIa Arm can commence providing that a meaningful clinical response (partial or 
complete tumour response as determined by RECIST criteria) has occurred in some patients in 
the Phase Ib Arm. Up to a maximum of 12 patients can be recruited of similar tumour type and 
disease status as the Phase Ib patients showing the clinical response and form the basis of 2 new 
patient cohorts. 
 
 

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8 STUDY PARTICIPANTS 
8.1 STUDY POPULATION 
Patients with refractory solid tumors that have failed standard treatment options. 
 
8.2 INCLUSION CRITERIA 
Patients must fulfill all of the following inclusion criteria to be eligible to enroll into the study: 
1. Provision of informed consent. 
2. Male or female ≥18 years of age. 
3. Histologic or cytologic confirmed locally advanced or metastatic cancer that has no 
standard therapeutic alternatives. 
4. At least 1 measurable lesion by CT/MRI scan. 
5. ECOG Performance status 0-1 (Appendix A). 
6. A minimum life expectancy of 12 weeks.  
7. 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  
8.  Female patients who are known to be capable of conception should have a negative 
serum pregnancy test (beta-human chorionic gonadotropin (β-hCG)) within 1 week of 
starting the study. 
9. All potentially fertile patients will agree to use an effective form of contraception during 
the study and for 90 days following the last dose of NOX66 (an effective form of 
contraception is defined as an oral contraceptive or a double barrier method. 
10. 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 Grade 1. 

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11. At least 21 days must have elapsed prior to Day 1 Cycle 1 since radiotherapy (limited 
palliative radiation is allowed > 2 weeks), immunotherapy or 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. Patients who are pregnant or breastfeeding.  
2. Tumor involvement of the Central Nervous System (CNS):  
• Patients with treated and stable CNS metastases may be eligible to participate after 
discussion and approval from the Medical Monitor. 
3. Uncontrolled infection or systemic disease.  
4. 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.  
5. Patients with QTc of > 470 msec on screening ECG. (If a patient has QTc interval >470 
msec on screening ECG, the screening ECG may be repeated twice (at least 24 hours 
apart). The average QTc from the 3 screening ECGs must be <470 msec in order for the 
patient to be eligible for the study.  
6. Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited 
palliative radiation is allowed > 2 weeks).  
7. Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy 
regimens given continuously or on a weekly basis with limited potential or delayed toxicity 
within the last 2 weeks.  
8. Any situation where the use of suppository therapy is contra-indicated or impractical (eg. 
chronic diarrhea, colostomy, ulcerative colitis). 
9. No concurrent systemic chemotherapy or biologic therapy is allowed.  
10. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated 
or both).  
11. History of solid organ transplantation.  
12. Psychiatric disorder or social or geographic situation that would preclude study 
participation.  

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13. Known unsuitability for treatment with carboplatin including renal disease where there is 
impaired glomerular filtration rate (GFR). 
 
8.4 STUDY WITHDRAWRAL 
It is planned that all enrolled patients will complete 1 treatment cycle at their assigned dose level. 
The patient can continue on idronoxil treatment at their allocated dose level weekly after Cycle 
1 until demonstrated progressive disease according to Investigator’s judgement, or a study 
withdrawal criterion is met. 
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 NOX66;  
• a DLT as defined in Section 10.1.4;  
• an adverse event related to idronoxil 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 therapy, and, if so, this must be reported in accordance with the procedures 
in Section 14.2.  
 
8.5 PATIENT REPLACEMENT 
Patients who cannot be evaluated as part of the efficacy analysis may be replaced in the study 
up to total of 16 evaluable patients.  
Replacement will occur at end of all safety cohort assessments and patient may be enrolled at 
the highest tolerated dose level, commencing with treatment cycle 1 of Phase 1b. 
 
 

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9 STUDY MATERIALS 
9.1  INVESTIGATIONAL STUDY PRODUCT 
9.1.1 Description and Formulation 
The drug substance, idronoxil, is manufactured by chemical synthesis and is produced as a single 
monomer. Idronoxil is manufactured to c-GMP (< 99% purity) specifications. 
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 standard (commercial) fatty acid base (MBK) to yield suppositories with an 
approximate weight of 2.2 gm and containing 400 mg drug substance. MBK is a common 
suppository base for a wide range of marketed drugs and the methods of manufacture, moulding, 
lubrication and packaging are standard. 
9.1.2 Presentation, Storage and Handling 
Presentation: NOX66 is presented as a solid dosage form suppository for rectal delivery.  
NOX66 suppository product will be provided directly by Noxopharm Ltd, the Sponsor. 
Storage and Handling: Boxes of NOX66 suppository should be stored at the study center in a 
secure area with limited access at 2-8°C (refrigerate), and protected from light. Any breach of 
investigational product storage conditions should be notified to the Sponsor on detection, and 
the study drug should be quarantined until the Sponsor authorizes usage or otherwise. 
NOX66 suppository is not expected to pose any significant 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 toxicity of between 300 to >2000 mg/kg body weight. The product also is contained within 
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9.1.3 Labelling 
NOX66 suppository is presented in plastic sleeves in boxes. Each box contains 15 suppositories 
intended to provide 14 single doses, plus 1 spare dose. 
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 suppository study product will be provided directly by Noxopharm Ltd, the Sponsor. 
Patients are to be given the requisite number of boxes of suppositories on Day 1 of the Treatment 
Cycle. Patients to return previously dispensed boxes at following visit for in-clinic administration 
and accountability. 
The number of boxes of study product (NOX66) to be dispensed will vary with the NOX66 
Treatment Regimen as shown in Table 1. 
 
 
 

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Table 1. Number of Boxes of NOX66 to be Dispensed per Treatment Regimen 
Idronoxil  
cohort 
Run-In Arm 
No. of boxes 
Combination Arm 
No. of boxes 
 Cohort 1 
1 
1 per 2 cycles 
Cohort 2 
2 
1 per cycle 
 
9.2 INVESTIGATIONAL PRODUCT ADMINISTRATION 
NOX66 suppository will be self-administered rectally either once or twice daily. 
Patients will be provided with ‘Instructions for the Use of a Suppository’ for reference. 
 
9.3 DURATION OF STUDY TREATMENT 
Patients can continue to receive combination therapy of idronoxil and carboplatin at their 
allocated dose level for: 
• up to 6 (six) 28-day treatment cycles OR  
• until demonstrated radiologic and/or clinically assessed progressive disease OR  
• until another withdrawal criterion is met (See Section 7.4). 
 
9.4 TREATMENT DOSE MODIFICATIONS 
There will be no dose modification of idronoxil on the basis of body weight except where the 
patient exceeds 100 kg body weight in which case the dose of idronoxil may be increased (up to 
double) at the discretion of the investigator. 
If a patient experiences a ≥ Grade 3 adverse event assessed as causally associated with idronoxil 
during the Run-In phase, the patient should be withdrawn from the study. If a patient experiences 
a ≥ Grade 3 adverse event assessed as causally associated with idronoxil during the Combination 
Arm, the patient may continue on idronoxil treatment at their assigned dose provided: 
1) the adverse event has resolved to no more than Grade 2 by the time of commencement of 
the next Treatment Cycle; 
2) a treatment break of > 2 weeks due to an unresolved adverse event will require 
discontinuation of study treatment. 
 

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9.5 ACCOUNATBILITY FOR CLINICAL SUPPLIES 
The Principal Investigator 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 the Investigator will destroy NOX66 suppositories 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 
suppositories 
to 
be 
used 
other 
than 
as 
directed 
by 
this 
protocol. 
 
9.6 CONCOMITANT MEDICATION 
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, but 
this again is to be confirmed with the Sponsor medical monitor prior to enrolment in the Study.  
Patients are not permitted any other experimental drugs treatments. 
Supportive care measures and symptomatic treatment for symptom control or drug-related 
toxicity are permitted including analgesics, etc. Erythropoiesis-Stimulating Agents (ESAs) are 
permitted but other hematopoietic growth factors are not. Although prophylactic anti-emetics 
and anti-diarrhoeals (eg. loperamide) are not permitted, they will be allowed if the patient 
experiences nausea, vomiting or diarrhoea. 
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 CRF 
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 CRF at each 
patient visit. “All medications” should include prescription, over-the-counter (OTC) medications, 
dietary/nutritional supplements, and herbal products. 
 
 

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10 STUDY PROCEDURES AND VISITS SCHEDULE 
The following section contains a detailed description of all study visits and procedures.  
10.1 STUDY ARMS 
10.1.1 
Phase Ia (Run-in) Arm  
Sixteen (16) patients will be enrolled; 8 patients to be allocated to each of two Cohorts and 
administered idronoxil (NOX66 suppository) using a 2-step inter-patient dose escalation. There 
is no intra-cohort dose escalation. Table 2 shows the dosing schedule in terms of NOX66 product 
and the equivalent dosage of idronoxil. 
Table 2. NOX66/Idronoxil Dose Level Schema 
Treatment Regimen/ 
Cohort 
NOX66 Dosage 
Daily Idronoxil Dosage 
1 
One suppository, once daily 
400 mg 
2 
One suppository, twice daily (12-hourly) 
800 mg 
Patients remain on the same daily dosage of idronoxil throughout all arms of the Study. 
Idronoxil will be administered over a 21-day Treatment Cycle comprising daily NOX66 
administration for 14 consecutive days followed by 7 days of rest. 
Once Cohort 1 has enrolled 4 patients, further recruitment to that cohort will be suspended until 
the fourth evaluable patient completes 1 Treatment Cycle (including the 7-day rest period) and 
at least 3 of the 4 patients have not experienced any toxicity > Grade 2. The remaining 4 patients 
in Cohort 1 may then be recruited and start treatment. 
Cohort 2 patients may commence idronoxil treatment once all 8 Cohort 1 patients have 
completed 1 (21-day) Treatment Cycle and at least 6 of those patients have not experienced any 
toxicity > Grade 2. 
Where MTD is deemed to have been reached, up to 6 additional patients may be recruited into 
the particular cohort in order to confirm the tolerability of the MTD. However, it is not expected 
that MTD will be reached in this study. 
 
 
 

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Table 3. Dose escalation Decision Rules for Run-In Arm 
Number of patients with toxicity 
> Grade 2 (or DLT) at a given dose 
level during the Run-In Arm 
Escalation decision rules 
0 out of 4 
Remaining 4 patients in that cohort to be enrolled and to receive that 
dose level.  
2 out of 8 
Remaining 6 patients in that cohort to complete the Run-In phase and 
proceed to the Combination phase. 
Next cohort of patients may commence at the higher dose level 
1 out of 34 
 
• Enter at least 2 more patients at this dose level 
• If no further patients experience toxicity > Grade 2, patients to 
complete the Run-In Arm and proceed to the Combination Arm. Next 
cohort of patients may commence at the higher dose level. 
• If 1 or more of this group experience > Grade 2 toxicity (2 of 8 dosed 
at this group), then dose escalation is stopped and this dose declared 
the maximally administered dose. Two (2) to 3 additional patients will 
be entered at the prior lower dose level if only 3 patients were treated 
previously at that dose. 
≥ 2 out of 4 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose. Two (2) to 3 additional patients will be 
entered at the prior lower dose level if only 3 patients were treated 
previously at that dose. 
≤ 1 out of 6 additional patients at 
highest 
dose 
level 
below 
the 
maximally administered dose 
This dose is the MTD and is generally the recommended dose to be used 
in Phase 2 clinical trials. At least 6 patients must be entered at this dose. 
Note – this is only applicable if DLTs are experienced in the study in order 
to determine the MTD. 
In the event of toxicity > Grade 2 in any Cohort 1 patient, the idronoxil dosage will be halved by 
reducing the dosage to 1 NOX66 suppository every second day. If toxicity > Grade 2 persists, the 
patient will be removed from the Study. 
In the event of toxicity > Grade 2 with Idronoxil in any Cohort 2 patient and where the Investigator 
is confident that the toxicity is related to Idronoxil, the patient will revert to the lower dosage 
form and will remain at that dosage level for the completion of the 14-day Run-In period of 
treatment and will stay on that dosage level in the Combination Arm of the study. If toxicity > 
Grade 2 persists, the patient will be removed from the Study. 
10.1.2 
 Phase Ib (Combination) Arm  
As each patient completes 1 Treatment Cycle of the Run-In Arm, they will be offered the 
combination treatment and may commence that combination treatment immediately providing 

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that there is no residual toxicity > Grade 1 or in the opinion of the Investigator has recovered 
from any Study-associated toxicity. Each patient will receive the same idronoxil dosage as they 
received in the Run-In Arm. A Treatment Cycle is 28-days. 
Idronoxil treatment will be daily for 7 consecutive days, commencing on Day 1 and continuing 
until Day 7.  
Carboplatin treatment will be administered intravenously on Day 2 of the Treatment Cycle, 
starting with a carboplatin dosage of AUC=4 for the initial 3 Treatment Cycles, before proceeding 
to an AUC=6 for up to 3 remaining Treatment Cycles. 
The maximum dosage of carboplatin that may be administered per Treatment Cycle is 600 mg 
(AUC=4) and 900 mg (AUC=6). 
Patients can receive up to 6 treatment cycles of combination therapy at the discretion of the 
Investigator provided that the patient is not experiencing DLT and the patient, in the opinion of 
the Investigator, is not experiencing disease progression. 
DLT during the Combination Arm of the Study will be managed as a result of discussion between 
the Investigator, the Medical Monitor and the Sponsor and could involve withholding of idronoxil 
and/or carboplatin until the patient recovers, and/or a reduction in the dosage of idronoxil 
and/or carboplatin through a change to a lower idronoxil and/or carboplatin dosage. 
If DLT recurs on re-introduction of treatment, the future of that patient is to be discussed with 
the Medical Monitor. 
If a second patient develops a DLT within any treatment regimen, then dose escalation will cease 
and the prior dose level will be declared the MTD for the combination therapy.  
10.1.3 
Phase IIa Arm 
This Arm can be activated where, in the opinion of the Principal Investigators and the Sponsor, 
sufficiently meaningful clinical responses have occurred in the Phase Ib Arm of the Study to 
warrant additional patient enrolment. 
There will be a maximum of 2 additional cohorts. Each cohort will comprise up to an additional 
10-12 patients with a specific form of cancer. The nature of these 2 additional Phase IIa cohorts 
will be determined by agreement between the Principal Investigators and the Sponsor. 
Patients will be treated with a combination of idronoxil and carboplatin using one of the same 
treatment schedules as used in the Phase Ib Arm of the Study. Which of the 4 
idronoxil/carboplatin dosage combinations that forms the Phase Ib Arm dosage matrix to be used 
in the Phase IIa Arm, is something that will be determined by agreement between the Principal 

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Investigators and the Sponsor. 
Patients will receive treatment for a maximum of 6 Treatment Cycles provided that the patient 
is not experiencing DLT and the patient, in the opinion of the Investigator, is not experiencing 
disease progression. 
Patients will be followed for safety and tolerability, and will be monitored and assessed by 
laboratory testing values as outlined in Section 10.2. 
10.1.4 
Definition and Determination of Dose Limiting Toxicity (DLT) and Maximum 
Tolerated Dose (MTD). 
The Maximum Tolerated Dose (MTD) of idronoxil as a monotherapy in the Phase Ia Run-In Arm 
will be defined as the dose level immediately below the dose level at which 2 of the first 4 patients 
per cohort (or at least 3 of 8 patients) during the first cycle of that particular Treatment Regimen 
experience DLT (related to therapy). Additional patients will be recruited so that at least 6 
patients are treated at the designated MTD, with no more than 1 DLT observed among the 6 
patients. The MTD will be defined in terms of NCI-CTC graded toxicity during the patients’ 
treatment cycle (21 days). 
A dose limiting toxicity (DLT) will be defined as any one of the following occurring during the first 
treatment cycle 1: 
• NCI-CTCAE ≥ Grade 3 neutropenia lasting ≥ 5 days OR febrile neutropenia (fever ≥ 38.5oC) 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with bleeding;  
• NCI-CTCAE ≥ Grade 3 abnormal laboratory values (except neutropenia and 
thrombocytopenia) that are assessed as clinically significant and causally associated with 
NOX66;  
• NCI-CTCAE ≥ Grade 3 non-laboratory toxicity that is assessed as causally associated with 
NOX66; (excluding alopecia, rash, nausea, diarrhea, and vomiting if controlled with 
standard supportive therapy);   
Once any DLT is reported, at least two more patients will be enrolled at the same dose level. 
Escalation will continue only if a DLT is limited to one of 4 patients. If a DLT occurs in 2 or more 
patients, further dose escalation will cease and the MTD will be the next lower level. 
 
 
 

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10.2 CLINICAL AND LABORATORY ASSESSMENTS 
10.2.1 
Demographic and Other 
A medical history will be obtained at screening. Medical history will include demographic data 
(e.g., date of birth, race/ethnicity). In addition, medical information will be recorded, including:  
• 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. 
10.2.2 
Safety 
The safety and tolerability of idronoxil will be assessed by monitoring and evaluation of clinical 
laboratory investigations as below: 
• Physical examination, inclusive of Eastern Cooperative Oncology Group (ECOG) 
performance status. 
• Vital signs including height (screening only), weight, standing and supine blood pressure, 
resting pulse rate, body temperature and respiratory rate. 
• Complete Blood Count (CBC) and Chemistry including: white blood cells with differentials, 
red blood cells, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
platelets, sodium, potassium, calcium, creatinine, total protein, albumin, bilirubin (total, 
direct), AST/SGOT, ALT/SGPT, alkaline phosphatase (ALP); urinalysis (dipstick). Urine 
microscopy will be performed if urinalysis values are out of range and the investigator 
deems that the microscopy is clinically warranted. 
Non-fasting samples for clinical laboratory analysis will be collected by a qualified staff 
member 
• 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. 
• Blood-based pregnancy tests will be performed on female subjects at Screening and End 
of Study visit 
• Adverse event (AE) monitoring using the National Cancer Institute Common Terminology 
Criteria for Adverse Events. 
Haematology, clinical chemistry and urinalysis will be performed by the site’s local accredited 
laboratories. 

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10.2.3 
Pharmacokinetic and Biomarker 
Idronoxil levels will be assayed both in plasma samples and 24-hour urine samples collected from 
patients in both the Phase Ia and Phase Ib Arms of the Study. See section 10.4.6. 
Biomarkers (ceramide, sphingosine kinase and ENOX 2 levels) will be measured in the same 
plasma samples collected for pharmacokinetic analysis. See section 10.4.7. 
Plasma collection and 24-hour urine collection procedures are outlined in APPENDIX B. 
Idronoxil and biomarker assays will be undertaken by the Sponsor performed by a designated 
laboratory. 
 
10.3 ASSESSMENT OF DISEASE STATUS 
Disease status will be assessed by standard RECIST criteria and ECOG Score. Objective responses 
will be recorded and reported. 
10.3.1 
Radiologic Assessments 
Baseline radiology by CT or MRI with contrast should be performed as close as possible to the 
start of treatment, but no longer than 28 days (4 weeks) prior to Cycle 1, Day 1. For the purposes 
of this study patients should be re-evaluated at the Investigator’s discretion, but at a minimum 
of every 12 weeks. The radiologic images should be performed consistently for the areas of 
disease involvement taken for the study evaluation. If the patient has achieved an Objective 
Response, a confirmatory scan will need to be performed 4 weeks after the response has been 
noted per RECIST criteria. 
Only those patients who have measurable disease at baseline, have received at least one Phase 
Ib cycle (28 days) of therapy, and have had their disease re-evaluated will be evaluable for 
response. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable).  
10.3.2 
Assessment of Response in Patients with Measurable Disease 
Assessments of disease response and progression should be made according to the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009).  
 

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10.4 STUDY VISITS 
10.4.1 
Screening 
The purpose and the procedures of the study will be fully explained to participants at the 
screening visit by the Principal Investigator and support staff and every patient approached 
regarding the study will be provided with the Informed Consent Form (ICF). Patients wishing to 
enroll in the study will sign the ICF prior to initiating any study related investigations or 
procedures. Radiological scans performed prior to consent can 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. 
All screened patients who sign the informed consent form (ICF) must be recorded on the 
Screening/Enrollment Log. If a subject who signs an ICF is not enrolled in the study, please provide 
the reason for exclusion on the log. The Screening/Enrollment Log will be retained within the 
Investigator Site File. 
The screening visit should occur at least 7 days before the commencement of NOX66 treatment. 
The following procedures are to be performed at the screening visit: 
• Review and sign Informed Consent Form  
• Review Inclusion and Exclusion Criteria  
• Review and record medical history including previous anti-cancer therapy  
• Physical examination  
• Determination of ECOG performance status (APPENDIX A) 
• Vital signs 
• 12-lead ECGs will be taken in triplicate, within 5 minutes of each other (over 15 minutes) 
• Complete Blood Count  
• Serum β-hCG pregnancy test (if female is of child bearing potential) 
• Review and record all concomitant medications 
• Tumor imaging (CT or MRI), including area of disease involvement. Note: tumor imaging 
may be performed anytime within 28 days of Cycle 1 Day 1 
 
 
 
 
 
 
 

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Table 4. Schedule of Assessments – SCREENING 
Obtain Informed Consent  
X 
Review Inclusion/Exclusion Criteria 
X 
Medical History 
X 
Physical Examination (PE) 
X 
12 Lead ECG  
X 
ECOG Performance Status 
X 
Vital Signs  
X 
Clinical laboratory tests 
 
      Complete Blood Count (CBC)  
X 
      Serum chemistry  
X 
      Pregnancy test (if applicable)  
X 
      Urinalysis (dipstick) 
X 
Concomitant medication review 
X 
Tumour imaging  
X 
 
 
10.4.2 
Phase Ia (Run-In) Arm Schedule of Procedures 
The procedures in this arm of the Study are summarized in Table 5. 
 
Table 5.  Schedule of Assessments -Phase Ia (Run-In) Arm 
Study Day   
1 
88 
15 
219 
 
Physical Examination (PE) 
X 
X 
X 
 
12 Lead ECG 1 
X 
X 
X 
 
Vital Signs 2 
X 
X 
X 
 
Clinical laboratory tests 
 
 
 
 
      Complete Blood Count (CBC) 3 
X 
X 
X 
 
      Serum chemistry 3 
X 
X 
X 
 
      Urinalysis (dipstick) 3 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
PK /Biomarker sampling 
X4 
X5 
X6 
 
Urine collection 7 
X 
X 
X 
 
Adverse events/toxicity assessment  
X 
X 
X 
X 
Dispense study drug 
X 
 
X 
 
1 ECG conducted 1-hour post NOX66 dosing on Days 1 and 8; any time Day 15.  
2 Vital signs = blood pressure, pulse, respiratory rate and body temperature. 
3 See Section 6.4 for list of blood tests. 
4 Plasma for PK analysis to be collected (Day 1) at t = 0, 30 min, 1 hr and 2 hr post-dosing. 
5 Plasma for PK analysis to be collected (Day 8) at t = 0, 1 hr and 2 hr post-dosing. 
6 Plasma for PK analysis to be collected (Day 15) at 24 hr post-dosing. 
7 24-hr urine sample to be collected starting from the time of NOX66 dosing on Day 1. 
8 Return study drug for in-clinic administration 
9 Phone call to confirm dose level and continuation to Phase1b.  
 
 

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10.4.3 
Phase Ib (Combination) Arm and End of Study Schedule of Procedures 
The procedures in this arm of the Study are summarized in Table 6. 
 
Table 6. Schedule of Assessments -Phase Ib (Combination) Arm 
 
Commencing 
Treatment Cycle 
Second and 
subsequent treatment 
cycles 
 
Study Day 1  
12 
23 
74 
15 
1 
2 
7 
15 
End of 
Study9 
Physical Examination (PE) 
 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 5 
 
X 
X 
 
 
X 
 
 
X 
ECOG Performance Status 
 
X 
X 
X 
 
 
X 
X 
X 
Vital Signs 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests 
 
 
 
 
 
 
 
 
 
      Complete Blood Count (CBC)  
 
X 
X 
X 
X 
 
X 
X 
X 
      Serum chemistry  
 
X 
X 
X 
X 
 
X 
X 
X 
      Pregnancy test (if applicable) 
 
 
 
 
 
 
 
 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
X 
Tumour imaging 7 
 
 
 
 
 
 
 
 
 
PK/Biomarker sampling 8 
 
 
X 
 
 
 
X 
 
 
Adverse events/toxicity assessment  
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
 
 
 
X 
 
 
 
 
1 There is ± 1-day window allowable for each clinic visit. 
2 Day 1: Commence NOX66 treatment 
3 Day 2:  Return study drug for in-clinic administration; Carboplatin treatment 1-hour post-NOX66 administration;  
4 Day 7: Return study drug for in-clinic administration and conclude NOX66 treatment 
5 ECG 1-hour post-NOX66 administration 
6 Vital signs: = weight, blood pressure, pulse, respiratory rate and body temperature.  
7Tumor burden to be assessed by CT/MRI according to the Investigator’s judgement at minimum every 12 weeks. 
Confirm objective response in 4 weeks.  
8 See Section 10.4.6 - 10.4.7 for the timing of collection of blood and urine for PK and blood for biomarker analyses.  
9 +28 – 33 days after last dose of Carboplatin treatment 
 
10.4.4 
NOX66 Dosing Schedules 
 
Table 7. Schedule of NOX66 Treatment in Phase Ia (Run-In) Arm 
Study Day   
  1-7 
 8-14 
  15-21 
NOX66  
  X 
 X 
  Rest 
 
Table 8. Schedule of NOX66 Treatment in Phase Ib (Combination) Arm per Cycle 
Study Day   
1 
2 
3-7 
8-28 
NOX66  
X 
X 
 X 
Rest 
Carboplatin 
Rest 
X 
Rest 
Rest 
 
 

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10.4.5 
Phase IIa Arm Schedule of Procedures 
The procedures in this arm of the Study are summarized in Table 9. 
 
Table 9. Schedule of Assessments - Phase IIa Arm 
 
Commencing 
Treatment Cycle 
Second and 
subsequent treatment 
cycles 
 
Study Day 1  
12 
23 
74 
15 
1 
2 
7 
15 
End of 
Study9 
Physical Examination (PE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 5 
 
 
X 
 
 
X 
 
 
X 
ECOG Performance Status 
X 
 
X 
X 
 
 
X 
X 
X 
Vital Signs 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests 
 
 
 
 
 
 
 
 
 
      Complete Blood Count (CBC)  
X 
 
X 
X 
X 
  
X 
X 
X 
      Serum chemistry  
X 
 
X 
X 
X 
  
X 
X 
X 
      Pregnancy test (if applicable) 
 
 
 
 
 
 
 
 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumour imaging 7 
 
 
 
 
 
 
 
 
 
Biomarker sampling 8 
 
 
X 
 
 
 
X 
 
 
Adverse events/toxicity assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
 
 
 
X 
 
 
 
 
1 There is ± 1-day window allowable for each clinic visit. 
2 Day 1: Commence NOX66 treatment 
3 Day 2: Carboplatin treatment 1-hour post-NOX66 administration 
4 Day 7: Conclude NOX66 treatment 
5 ECG 1-hour post-NOX66 administration 
6 Vital signs: = weight, blood pressure, pulse, respiratory rate and body temperature.  
7Tumor burden to be assessed by CT/MRI according to the Investigator’s judgement at minimum every 12 weeks.       
  Confirm objective response in 4 weeks.  
8 See Section 10.4.7 for the timing of collection of blood for biomarker analyses.  
9 +28 – 33 days after last dose of Carboplatin treatment 
 
 
 
 
 
 
 
 
 
 
 
 

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10.4.6 
Pharmacokinetic Analysis 
Phase Ia (Run-In) Arm: All patients in the Phase Ia (Run-In) Arm will have plasma and urine 
analyses conducted over the 21-day treatment cycle. 
Blood to be collected on Days 1, 8 and 15 at the following times (Table 10):  
Table 10. PK Blood Sampling Schedule for Phase Ia (Run-In) Arm 
Day Sampling time in relation to NOX66 administration 
1 
t = 0 (pre-dose), then 0.5, 1, and 2 hr post-dose* 
8 
t = 0 (pre-dose), then 1 hr and 2 hr post-dose* 
15 
t = 24 hr post-dose  
*Post dosing sampling may be taken following administration of the first suppository for Cohort 2 patients. 
24-hour urine will be collected on Days 1, 8 and 15, commencing from the time of NOX66 
administration on those days and returned at following visit day. 
Phase Ib (Combination) Arm: Blood samples to be collected from all patients on Day 7 of each 
Treatment Cycle at t = 1hour post-dosing. Post dosing sampling may be taken following 
administration of the first suppository for Cohort 2 patients. 
10.4.7 
Biomarker Analysis 
Blood for biomarker analysis will be collected at the following times: 
Phase Ia (Run-In): sample collected from all patients on Days 1, 8 and 15 as follows: 
 
Table 11. Biomarker Blood Sampling Schedule for Phase Ia (Run-In) Arm 
Day Sampling time in relation to NOX66 administration 
1 
t = 0 (pre-dose), then 1 hr post-dose* 
8 
t = 1 hr post-dose* 
15 
t = 24 hr post-dose  
*Post dosing sampling may be taken following administration of the first suppository for Cohort 2 patients. 
Phase Ib: sample collected from all patients on Day 7 of each cycle, 1hour post dose. Post dosing 
sampling may be taken following administration of the first suppository for Cohort 2 patients. 

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11 METHODS OF ASSIGNMENT OF INTERVENTION 
11.1 ALLOCATION OF TREATMENT 
NOX66-001A is a Phase I open-label, non-randomized, dose-escalation study of idronoxil in 
suppository form. Patients will be consented, screened and identified as eligible for the study by 
the Investigator at each site. Eligible patients will be allocated a number for identification on the 
electronic Case Report Form (eCRF) and for patient tracking purposes. The patients’ ID will be 
determined by a one-digit site number, plus a two-digit patient number, which will be allocated 
chronologically and will be site specific e.g. first patient at site 1 will be number: 1-01, then 
sequentially 1-02, 1-03 etc. Likewise, site 2 first patient would be 2-01, 2-02, etc. Study numbers 
will only be used once and will not be reallocated to any other patient during the study. 
Patients should begin protocol treatment within 72 hours of enrollment. Issues that would cause 
treatment delays longer than 72 hours should be discussed with the Sponsor. If a patient does 
not proceed to receive protocol therapy following enrollment, the patient’s study enrollment 
may be cancelled and the patient will be considered a screen failure. The Sponsor should be 
notified of screen failures as soon as possible. 
Sites will be notified by the Sponsor’s Medical Monitor that enrollment to a cohort has been 
suspended so no further patients are recruited, until it is determined that either additional 
patients will be enrolled at the existing dose level or that enrollment to the next cohort may 
commence. 
11.2 BLINDING AND UNBLINDING 
Idronoxil will be administered at escalating doses in an open-label fashion. Patients will be 
allocated to 1 of 2 cohorts. No randomization or stratification is required. 
 
 

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12 DATA COLLECTION AND MANAGEMENT 
12.1 METHODS 
The Principal Investigator must ensure there will be primary source documentation for all patient 
data collected as part of the study, and the data will not be recorded directly onto the CRFs 
without 
the 
availability 
of 
such 
primary 
documentation, 
except 
for 
cases 
in 
which the Sponsor has predetermined that direct data entry into specified pages of the patient’s 
CRF is appropriate. 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 will be responsible for the timeliness, completeness, and accuracy of 
the information entered on the CRF. The Principal Investigator will provide 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. 
12.1.1 
Case Report Form 
All information relative to the study will be recorded into a 21 CFR part 11 FDA compliant 
electronic Case Report Form (eCRF).  Data corrections will be entered by the authorised site 
personnel. 
12.1.2 
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 in accordance with National regulations. 
 
12.2 DATA MANAGEMENT 
12.2.1 
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). 

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12.2.2 
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 
 
 

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13  STATISTICAL SECTION 
13.1 SAMPLE SIZE 
This is a sighting study intended to determine the safety of idronoxil (as NOX66 suppository 
dosage formulation) in combination with carboplatin, and to provide guidance as to the dosage 
combination of the two drugs that will be taken into later studies. A minimum of 8 patients per 
combination is considered adequate. 
 
13.2 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. 
The primary objectives of this study are to determine  
(a) the tolerability, adverse event profile and any dose limiting toxicities (DLTs) of idronoxil 
(as NOX66) in combination with carboplatin in patients with refractory solid tumors, and 
(b) the ability of idronoxil (as NOX66) in combination with carboplatin to deliver a meaningful 
anti-cancer effect in refractory tumours considered unlikely to respond to carboplatin. 
Secondary objectives are:  
1) to characterize the pharmacokinetic profile of idronoxil administered rectally as NOX66, 
and 
2) to determine any correlation between biomarkers of idronoxil biological activity and any 
clinical anti-tumor activity or toxicity observed in patients treated with NOX66. 
These objectives are to be addressed in the context of an open-label, dose-escalation study; 
therefore, statistical hypothesis-testing will not be performed, and analyses will be primarily 
descriptive in nature. 
All patients will be included in the safety evaluation. Data will be presented by dose cohort. Data 
from Study NOX66-001A will be used to guide dosing for future Phase II trials. 
Populations for Analysis: There will be three study populations defined for this study. 
The safety population will consist of all patients who received at least one dose of idronoxil. This 
population will be used in all safety summaries. 
The efficacy population will consist of all patients with measurable or evaluable disease at 
baseline who complete at least 1 cycle of treatment and undergo at least one follow-up tumor 

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evaluation. 
The pharmacokinetic/biomarker population will be a subset of the safety and efficacy 
populations and consist of all patients who have sufficient idronoxil plasma data for analysis. All 
such patients will be evaluated unless significant protocol deviations have impacted the data. 
Changes to the procedures, which may impact the quality of pharmacokinetic data, will be 
considered significant protocol deviations. Examples include sample processing errors that lead 
to inaccurate bio- analytical results and/or inaccurate dosing on the day of pharmacokinetic 
sampling. 
General Methodology: In general, data will be summarized by using counts and percents for 
discrete parameters, and by descriptive statistics (number of observations, mean, standard 
deviation, median, minimum and maximum) for continuous parameters. Subject disposition and 
baseline characteristics will be presented by dose cohort for all treated patients. Data will be 
analysed as collected. No imputation of missing data is planned. All collected data will be 
presented in the data listings by dose cohort. 
Baseline Comparisons and Patient Disposition: Demographic and baseline disease characteristic 
data summarization will be performed in order to descriptively assess the comparability of dose 
cohorts. Data to be tabulated will include demographic features such as gender, age, and race, 
as well as disease specific status and medical history. The number and percentage of patients 
who complete the study or who withdraw for any reason will be presented by dose cohort. 
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, ECG findings, physical examinations, vital signs, and 
changes in ECOG status. A copy of CTCAE Version 4.03 scoring system may be downloaded from:  
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 ECG findings and physical 
examinations, will be summarized throughout the study by visit for each dose level for all treated 
patients. 

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ECG parameters at each time point will be presented by patient and by time point. The results 
will be presented by dose cohort. 
Efficacy Analysis: Tumor measurements will be assessed by radiologic methods at baseline and 
at subsequent intervals at the discretion of the Investigator but not greater than every 12 weeks. 
Efficacy variables will include overall response, duration of objective response, time to 
progression, progression free survival (PFS), and overall survival. Response and progression will 
be assessed according to RECIST (Eisenhauer et al., 2009). 
Continuous data will be summarized by descriptive statistics, including sample size, mean, 
standard deviation, median and range. Categorical data will be summarized by the number and 
percentage of patients. For the time-to-event endpoints, Kaplan-Meier estimates will be plotted. 
Median event time and the associated 95% confidence interval will be provided. In addition, all 
the data will be presented in the data listings. The final statistical analysis for the study will be 
scheduled when all patients have completed at least one course of study drug administration, 
have reached a study endpoint (e.g., DLT or disease progression), and have at least 28 days of 
follow- up. 
Best overall response, duration of objective response (complete response or partial response), 
PFS, time to progression and overall survival will be listed for all patients with measurable or 
evaluable disease by dose level. Any patient with insufficient data to determine response will be 
classified as a non-responder. Among patients with an objective response, duration of objective 
response will be defined as the time from the initial CR or PR to the time of disease progression 
or death on study, whichever occurs first. For patients who are alive and have not experienced 
disease progression on study, duration of objective response will be censored at the day of the 
last tumor assessment. Time to disease progression is defined as the time from the first day of 
study drug administration (Day 1) to disease recurrence or progression on study. Progression free 
survival (PFS) is defined as the time from the first day of study drug administration (Day 1) to 
disease recurrence or progression, or death on study. Patients who are alive and disease 
progression-free will be censored at the date of last disease evaluation. 
Pharmacokinetics: Plasma and 24-hour urine levels of idronoxil and idronoxil metabolites 
(idronoxil glucuronide, idronoxil sulphate) will be measured. Pharmacokinetic parameters will 
minimally include Cmax, Tmax, AUC0-24hr, AUC0-∞, and t1/2 and be calculated using standard analysis. 
Descriptive results will be presented for the pharmacokinetic parameters by dose cohort. 
In the event that PK concentrations are not detectable at the time points necessary and a 
meaningful PK curve (i.e. concentration vs time) cannot be estimated, descriptive statistics will 
be used to summarize PK concentration. 

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Concomitant medications: Concomitant medications will be listed by dose cohort for all patients. 
 
13.3 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. 
13.4 INTERIM AND ADDITIONAL ANALYSIS 
None. 
 
 

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14 MONITORING 
14.1 MONITORING OF CASE REPORT FORMS 
The study will be monitored by 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. 
 
14.2 SAFETY DATA MONITORING 
The Medical Monitor will review and evaluate all toxicities causally associated with idronoxil 
(NOX66). Once the fourth patient of Cohort 1 has completed 1 Cycle or when appropriate, 
depending on the DLTs experienced, a determination will be made that enrolment to this cohort 
continue. Once the eighth patient in Cohort 1 has completed 1 treatment cycle or when 
appropriate, depending on the DLTs experienced, the next dose level may commence. 
 
14.3 AUDITING 
Regulatory authorities, the HREC (Human Research Ethics Committee) equivalent 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 for quality assurance. The 
Investigator is obliged to facilitate this process by allowing full access. 
 
 
 
 

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15 ADVERSE EVENT REPORTING 
Adverse events (AE) 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 (Table 12) and outcome categories should be defined (Table 
13). 
15.1 DEFINITIONS 
15.1.1 
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. 
15.1.2 
SAE 
The definitions of SAEs are given below. The PI is responsible for ensuring that all staff involved 
in the trial are familiar with the content of this section. 
An SAE or reaction 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 
criteria for solid tumours), should not be reported as an SAE and must be approved by the 
Sponsor. 
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  

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• 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 12. 
15.1.3 
Guidelines for Determining Causality and Severity 
The criteria used for determining the relationship between the study drug/s and the Adverse 
Event are shown below: 
Table 12.  Adverse Event Relatedness Criteria to Study Drug 
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 13: Adverse Event Outcome Category 
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. 
 
15.2 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 treatment, 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). 
Deaths and other SAEs occurring > 30 calendar days after last study treatment 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 study trial treatment 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 
using the contact information below.  
Primary Contact 
Medical Monitor: Prof. Paul de Sousa 
Telephone #: +61 2 9350 3910 
Mobile #:      +61 404 003 220 
Email#:   P.DeSouza@westernsydney.edu.au           
Alternate Contact   
Study Manager: Marinella Messina 
Telephone #: +61 2 9144 2223; Fax #:   +61 2 9199 9600     
Mobile #:  +61 499 005 049 
  Email: marinella.messina@noxopharm.com 

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Pharmcovigilance (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. 
 
15.2.1 
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. 
15.2.2 
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 
Sponsor. 
15.2.3 
Sponsor SAE Reporting Requirements 
The Sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonization (ICH) guidelines, NHMRC 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 

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or fax within 7 calendar days after being 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. 
 
15.2.4 
Pregnancy 
If a study patient or a patient partner becomes pregnant while enrolled in the trial, a Pregnancy 
Form should be completed and faxed to the Sponsor expeditiously, irrespective of whether or 
not it meets the criteria for expedited reporting. Abortions (spontaneous, accidental, or 
therapeutic) must also be reported to the Sponsor. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting. The 
previous completed Pregnancy Form must be updated to reflect the outcome of the pregnancy. 
 
 

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16 CONDUCT OF STUDY 
16.1 HUMAN RESEARCH  
The Protocol and all other relevant study documents (informed consent etc) will be submitted to 
the local HREC peer site and then to the Georgian Ministry of Health for approval. 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. 
 
16.2 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). 
Compliance with these guidelines ensures compliance with the currently approved version of the 
Declaration of Helsinki latest version (October 2013) and any local legal and regulatory 
requirements. 
 
16.3 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. 
Notify the Human Research Ethics Committee (HREC) of all changes in the protocol, and provide 
documented approval of 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. 
16.3.1 
Protocol Violation and Reporting 
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: 

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• 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 the procedure described in 
Section 14.2. 
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. 
 
16.4 PROTOCOL AMENDMENTS 
With the exception of emergency situations, no changes or deviations in the conduct of this 
protocol will be permitted. Notify the Human Research Ethics Committee (HREC) of all changes 
in the protocol, and provide documented approval of 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. 
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. 
 
 

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17 PATIENT INFORMED CONSENT 
The proposed informed consent form contains the 20 elements required for the provision of 
informed consent as described in ICH E6 (R2) 4.8. and the Declaration of Helsinki. Additionally, 
the informed consent form has been reviewed and approved by the Sponsor, the HREC and as 
applicable by national regulatory authority 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. 
 
 
 
 

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18 DISCLOSURE OF DATA 
18.1 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 national health authorities, the Sponsor or delegate, 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 required by 
regulatory or legal inquiries. 
To fully evaluate patient safety issues that may arise during the study, Sponsor, or state and 
national 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 enrollment into the study that the patient’s Protected 
Health Information (PHI) obtained during the study may be shared with the study, Sponsor, state 
and national authorities, and HREC regulatory inspections(s). 
18.1.1 
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 national regulatory authorities/agencies. 
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 enrolment log (patient numbers and the corresponding 
patient names) to enable the records to be identified. 

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18.1.2 
Prior to Study Commencement 
Prior to the start of this study, all pre-investigational requirements must be met by the Principal 
Investigator and study site. These may include: 
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 national authority acknowledging and or approving 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 the 
protocol should be supplied. 
18.1.3 
Document Retention 
The Principal Investigator will retain copies of the following documents in a secure place for a 
period of at least 2 years after the last approval of a marketing application in an ICH region or at 
least 2 years after the formal discontinuation of the clinical development of the investigational 
product. These documents may be retained for a longer period by agreement with the Sponsor. 
These files must be made available for inspection upon reasonable request by authorised 
representatives of the Sponsor and the corresponding regulatory agencies for the purposes of 
regulatory approval.  
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 

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such transfer will be given in writing to the Sponsor. 
18.1.4 
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. 
18.1.5 
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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19 ADDITIONAL PATIENT CARE DURING POST-STUDY 
19.1 EMERGENCY CONTACT 
19.1.1 
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. 
19.1.2 
Sponsor 
In an emergency, the Principal Investigator should contact both the study Sponsor and the 
Monitor by telephone. 
 
19.2 Liability and Insurance 
With effect from the commencement of the study, the Sponsor will indemnify study participants 
according to the local institutional regulations for clinical study involvement. 
 
 
 
 
 
 
 

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20 APPENDICIES 
20.1 APPENDIX A  
20.1.1 
ECOG Performance Status* 
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, eg. 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. 
20.2 APPENDIX B 
20.2.1 
Procedure for Collection of Plasma Samples 
The patient does not have to fast prior to the taking of the PK samples.  
Plasma samples will be analysed by the Sponsor for levels of idronoxil and biomarkers. 
Draw blood from participant into a 5 mL K3 EDTA anti-coagulation blood collection tube provided 
in the sampling kit. Ensure adequate mixing between blood and EDTA by inverting tube back and 
forth for 30 seconds. Place tube on ice if the sample is not for immediate centrifugation. Samples 
must be centrifuged within 30 minutes of collection. 
• Label a 5 mL K3 EDTA tube and plasma collection tube with participant study number, 
initials, sample date and time of draw.  
• Centrifuge at 3000 rpm for 10 min (under refrigeration) within 30 minutes of blood 
collection.  
• Carefully separate plasma for transfer into two 2 mL screw top tubes that have been 
labelled with the participant study number, initials, sample date and time of draw.  

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• Place each of the tubes in two separate fiber board freezer boxes noting the position 
number of the well in the box and freeze immediately at – 20oC or 80oC. 
• Complete 2 separate inventory logs recording the specific sample position in each of 
the boxes on the corresponding inventory log line number. 
• One box of frozen samples should be batched and shipped monthly. Call the Study 
Manager to arrange a courier for transfer of specimens. The remaining box of frozen 
samples is to be retained at the study site until shipment is requested. 
 
20.2.2 
Procedure for Collection of Urine Samples 
Patients to be provided with Instructions for the Collection of 24-Hour Urine Samples.  
• Urine to be returned to hospital within 24 hours of collection. 
• Measure and record total volume. 
• Dispense approximately 5 aliquots into 2 screw-top tubes provided that have been 
labelled with participant subject number, initials and sample date. 
• Place each of the tubes in two separate fiber board freezer boxes noting the position 
number of the well in the box and freeze immediately at – 20oC or 80oC. 
• Complete 2 separate inventory logs recording the specific sample position in each of the 
boxes on the corresponding inventory log line number. 
• One box of frozen samples should be batched and shipped monthly. Call the Study 
Manager to arrange a courier for transfer of specimens. The remaining box of frozen 
samples is to be retained at the study site until shipment is requested. 
 
20.3 APPENDIX C 
20.3.1 
References 
Alvero AB, Brown D, Montagna M, Matthews M, Mor G (2007). Phenoxodiol-topotecan co- 
administration exhibit significant anti-tumor activity without major adverse side effects. Cancer 
Biol Ther. Apr;6(4):612-7.  
Alvero AB, Rossi P, Brown D, Leiser A, Kelly M, Rutherford T, Husband AJ, Mor G (2008). 
Phenoxodiol – a chemosensitizer in the midst of cancer chemoresistance. US Oncology. 24:39-
41.  
Brown D, Heaton A, Husband A (2008). Idronoxil. Drugs Fut. 33(10):844-860.  
de Souza PL, Russell PJ, Kearsley JH, Howes LG (2010). Clinical pharmacology of isoflavones and 
its relevance for potential prevention of prostate cancer. Nutr Rev. Sep;68(9):542- 55.  

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Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L., Sargent, D., Ford, R., Dancey, J., Arbuck, S., 
Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D., Verweij, 
J., 2009. New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (version 
1.1) European J. Cancer. 45: 228-247.  
Fotopoulou C, Vergote I, Mainwaring P, Bidzinski M, Vermorken JB, Ghamande SA, Harnett P, Del 
Prete SA, Green JA, Spaczynski M, Blagden S, Gore M, Ledermann J, Kaye S, Gabra H (2014). 
Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral 
phenoxodiol, a sensitizer of platinum cytotoxicity: the Phase III OVATURE multicentre 
randomized study. Ann Oncol 25:160-165. 
Herst PM, Petersen T, Jerram P, Baty J, Berridge MV. (2007). The antiproliferative effects of 
phenoxodiol are associated with inhibition of plasma membrane electron transport in tumor cell 
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