Clinical trial NCT04957290
Conditions: Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors
Keywords: Dose Escalation Dose Expansion Prostate-specific antigen Maximum tolerated dose Recommended Phase 2 dose
Sponsor: Noxopharm Limited
Start date: 2021-10-25; Completion date: 2023-06-07
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, recommended Phase 2 dose (RP2D), efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) and patients with metastatic castration-resistant prostate cancer (mCRPC), breast cancer (BC) and non-small-cell lung cancer (NSCLC) (Part 2) who are eligible for low-dose external beam radiotherapy (EBRT) for at least one symptomatic or minimally symptomatic lesion (for the prevention of symptoms).

Detailed description:
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The study design allows an exploration of different doses of NOX66 (800 mg, 1200 mg, 1600 mg and 2400 mg) with safety monitoring to ensure the safety of the patients. In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day cycle. From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest period on a 14-day cycle. Patients will continue to receive NOX66 on a cyclical basis until disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by the Investigator or the end of study is reached.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: NOX66 intervention 2: NOX66 intervention 3: NOX66 intervention 4: NOX66 intervention 5: NOX66 intervention 6: EBRT
Intervention descriptions: intervention 1: NOX66 800 mg daily (400 mg suppository twice daily \[BID\]). intervention 2: NOX66 1200 mg daily (600 mg suppository BID). intervention 3: NOX66 1600 mg daily (800 mg suppository BID). intervention 4: NOX66 2400 mg daily (1200 mg suppository BID). intervention 5: NOX66 RP2D intervention 6: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.

Protocol documents:
Prot_SAP_001.pdf: 
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Title Page 
Protocol Title: 
A Phase 1b/2a Multicenter Study of NOX66 and 
External Beam Radiotherapy in Patients with 
Metastatic Castration-resistant Prostate Cancer and 
Other Solid Tumors 
Compound: 
NOX66 (active ingredient: Idronoxil) 
Trade Name: 
Not applicable 
Indication: 
Metastatic castration-resistant prostate cancer and 
other solid tumors 
Study Sponsor: 
Noxopharm Limited 
PO Box 292 
Gordon, NSW 2072 
Australia 
Sponsor Protocol Number: 
NOX66-005 
Development Phase: 
Phase 1b/Phase 2a 
Regulatory Agency Identifying 
Number: 
154874 
Approval Date: 
Final 3.0, 21 Jan 2022 
 
 


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Sponsor Signatory: 
 
 
Dr Gisela Mautner 
Chief Medical Officer 
 
Date 
 
Medical Monitor Name and Contact Information will be provided separately. 
 
 


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Table of Contents 
 
Table of Contents ............................................................................................................................ 3 
1 
Protocol Summary .................................................................................................................... 8 
1.1 
Synopsis ................................................................................................................................ 8 
1.2 
Schema ............................................................................................................................... 27 
1.3 
Schedule of Activities ......................................................................................................... 31 
1.3.1 
Electrocardiogram Schedule ........................................................................................... 41 
1.3.2 
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1 and Part 2 ...... 42 
2 
Introduction............................................................................................................................. 44 
2.1 
Study Rationale .................................................................................................................. 44 
2.2 
Background......................................................................................................................... 45 
2.3 
Benefit/Risk Assessment .................................................................................................... 47 
2.3.1 
Risk Assessment ............................................................................................................. 47 
2.3.2 
Benefit Assessment ......................................................................................................... 49 
2.3.3 
Overall Benefit: Risk Conclusion ................................................................................... 50 
3 
Objectives and Endpoints ....................................................................................................... 50 
4 
Study Design ........................................................................................................................... 52 
4.1 
Overall Design .................................................................................................................... 52 
4.1.1 
Part 1 (Dose Escalation) ................................................................................................. 55 
4.1.2 
Part 2 (Dose Expansion) ................................................................................................. 57 
4.2 
Scientific Rationale for Study Design ................................................................................ 57 
4.3 
Justification for Dose .......................................................................................................... 59 
4.4 
End of Study Definition...................................................................................................... 59 
5 
Study Population ..................................................................................................................... 59 
5.1 
Inclusion Criteria ................................................................................................................ 60 
5.2 
Exclusion Criteria ............................................................................................................... 62 
5.3 
Screen Failures ................................................................................................................... 65 
5.3.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 65 
6 
Study Drug .............................................................................................................................. 65 
6.1 
Study Drug(s) Administered ............................................................................................... 65 
6.1.1 
Radiotherapy ................................................................................................................... 67 


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6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 67 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 68 
6.4 
Study Drug Compliance ..................................................................................................... 69 
6.5 
Concomitant Therapy ......................................................................................................... 70 
6.6 
Dose Modification .............................................................................................................. 70 
6.6.1 
Dose Modification of Radiotherapy ............................................................................... 72 
6.7 
Study Drug After the End of the Study .............................................................................. 72 
7 
Discontinuation of Study Drug and Participant Discontinuation ........................................... 72 
7.1 
Discontinuation of Study Drug ........................................................................................... 72 
7.1.1 
Safety Stopping Criteria: ................................................................................................ 72 
7.1.2 
Dose Escalation Rules and Safety Steering Committee ................................................. 73 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................... 77 
7.3 
Loss of Participants to Follow-Up ...................................................................................... 78 
8 
Study Assessments and Procedures ........................................................................................ 78 
8.1 
Efficacy Assessments ......................................................................................................... 79 
8.1.1 
Prostate-specific Antigen (PSA) Response and Progression (mCRPC only) ................. 79 
8.1.2 
Disease Control Rate ...................................................................................................... 80 
8.1.3 
Tumor Imaging Assessment ........................................................................................... 80 
8.1.4 
Eastern Cooperative Oncology Group Performance Status Score ................................. 82 
8.1.5 
Clinical Outcome Assessment ........................................................................................ 82 
8.1.6 
Morphine Administration and Analgesic Use ................................................................. 84 
8.1.7 
Skeletal-related Events and Symptomatic Skeletal Events Assessment ......................... 84 
8.1.8 
Progression-free Survival ............................................................................................... 84 
8.1.9 
Overall Survival .............................................................................................................. 84 
8.1.10 
Overall or Objective Response Rate ............................................................................... 84 
8.2 
Safety Assessments ............................................................................................................. 85 
8.2.1 
Administrative Procedures ............................................................................................. 85 
8.2.2 
Screening and Eligibility Assessments ........................................................................... 85 
8.2.3 
Dose-limiting Toxicity .................................................................................................... 87 
8.2.4 
Physical Examinations .................................................................................................... 87 
8.2.5 
Vital Signs ...................................................................................................................... 88 
8.2.6 
Electrocardiograms ......................................................................................................... 88 
8.2.7 
Clinical Safety Laboratory Assessments ........................................................................ 89 
8.2.8 
Radiotherapy Treatment Interruptions ............................................................................ 90 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 90 


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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 90 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 91 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 91 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 91 
8.3.5 
Pregnancy ....................................................................................................................... 92 
8.3.6 
Cardiovascular and Death Events ................................................................................... 92 
8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 93 
8.3.8 
Adverse Events of Special Interest ................................................................................. 93 
8.4 
Treatment of Overdose ....................................................................................................... 93 
8.5 
Pharmacokinetics ................................................................................................................ 93 
8.6 
Pharmacodynamics ............................................................................................................. 94 
8.7 
Genetics .............................................................................................................................. 94 
8.8 
Biomarkers ......................................................................................................................... 94 
8.9 
Archival and Fresh Tissue Biopsy ...................................................................................... 95 
8.10 Immunogenicity Assessments ............................................................................................ 95 
8.11 Health Economics or Medical Resource Utilization and Health Economics ..................... 95 
9 
Statistical Considerations........................................................................................................ 95 
9.1 
Statistical Hypotheses ......................................................................................................... 95 
9.2 
Sample Size Determination ................................................................................................ 96 
9.3 
Populations for Analyses .................................................................................................... 96 
9.4 
Statistical Analyses ............................................................................................................. 97 
9.4.1 
General Considerations .................................................................................................. 97 
9.4.2 
Participant Disposition ................................................................................................... 97 
9.4.3 
Participant Demographics and Baseline Characteristics ................................................ 97 
9.4.4 
Concomitant Medications ............................................................................................... 98 
9.4.5 
Treatment Exposure and Study Drug Compliance ......................................................... 98 
9.4.6 
Primary Endpoint(s) ....................................................................................................... 98 
9.4.7 
Secondary Endpoint(s) ................................................................................................... 99 
9.5 
Interim Analyses ............................................................................................................... 102 
9.6 
Data Monitoring Committee (DMC) ................................................................................ 102 
10 Supporting Documentation and Operational Considerations ............................................... 102 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .......................... 102 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 102 
10.1.2 
Financial Disclosure ..................................................................................................... 103 


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10.1.3 
Informed Consent Process ............................................................................................ 103 
10.1.4 
Data Protection ............................................................................................................. 104 
10.1.5 
Committees Structure ................................................................................................... 104 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 104 
10.1.7 
Data Quality Assurance ................................................................................................ 105 
10.1.8 
Source Documents ........................................................................................................ 107 
10.1.9 
Study and Site Start and Closure .................................................................................. 107 
10.1.10 Publication Policy ......................................................................................................... 108 
10.1.11 Protocol Approval and Amendment ............................................................................. 108 
10.1.12 Liability and Insurance ................................................................................................. 108 
10.2 Appendix 2: Clinical Safety Laboratory Tests ..................................................................110 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ..................................................................................................112 
10.3.1 
Definition of AE ............................................................................................................112 
10.3.2 
Definition of SAE ..........................................................................................................113 
10.3.3 
Recording and Follow-up of AE and SAE ....................................................................115 
10.3.4 
Reporting of SAE ..........................................................................................................117 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ............ 121 
10.5 Appendix 5: Tumor Imaging ............................................................................................ 125 
10.6 Appendix 6: European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire for Cancer Patients (EORTC-QLQ-C30) .................................................. 126 
10.7 Appendix 7: Brief Pain Inventory – Short Form .............................................................. 128 
10.8 Appendix 8: Patient Experience Questionnaire (PEQ) .................................................... 130 
10.9 Appendix 9: Functional Assessment of Cancer Therapy – Prostate (FACT-P) Version 4 134 
10.10 Appendix 10: Guidance for Low-Dose EBRT ................................................................. 137 
10.11 Appendix 11: Country-Specific Requirements ................................................................. 142 
10.12 Appendix 12: Abbreviations and Trademarks .................................................................. 143 
11 References............................................................................................................................. 147 
Investigator Agreement Page ...................................................................................................... 148 
List of Figures 
Figure 1–1: 
Study Design: Part 1 ............................................................................................. 27 
Figure 1–2: 
Study Design: Part 2 ............................................................................................. 30 


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List of Tables 
Table 1-1 
Schedule of Activities (SoA) – Part 1 and Part 2 .................................................. 31 
Table 1-2 
Electrocardiogram Schedule: Part 1 (All Patients) and Part 2 (Only for First 10 
Patients in Each Tumor Type) ............................................................................... 41 
Table 1-3 
Pharmacokinetic Sampling Schedule Following Morning Dose – Part 1 (All 
Patients) and Part 2 (Only for First 10 Patients in Each Tumor Type) ................. 42 
Table 1-4 
Pharmacodynamic Sampling Schedule – Part 1 and Part 2 (All Patients) ............ 43 
Table 1-5 
Optional Archival Tissue Collection and Fresh Biopsy Sampling Schedule – 
Part 1 and Part 2 (All Patients) ............................................................................. 43 
Table 3-1 
Objectives and Endpoints ..................................................................................... 50 
Table 4-1 
Proposed Doses for NOX66 (Part 1) .................................................................... 56 
Table 6-1 
Study Drug(s) Administered ................................................................................. 65 
Table 6-2 
Dose Modification of Study Treatment NOX66 ................................................... 71 
Table 6-3 
Management of NOX66 Treatment-related Toxicity ............................................ 71 
Table 8-1 
Eastern Cooperative Oncology Group Performance Status Score ........................ 82 
Table 9-1 
Populations for Analysis ....................................................................................... 96 
Table 10-1 
Protocol-Required Safety Laboratory Assessments .............................................110 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in 
Patients with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
Sponsor Protocol No.: NOX66-005 
Development Phase: Phase 1b/Phase 2a 
Sponsor: Noxopharm Limited 
Study Sites and Locations: Approximately 14 sites in Australia, United States and Europe 
Rationale: 
Idronoxil, which is the active ingredient of the NOX66 formulation, is a synthetic flavonoid 
derivative of genistein that inhibits external Ecto-NOX disulfide-thiol exchanger (ENOX) 2 to 
induce apoptosis.  ENOX2 inhibition activates the sphingomyelinase pathway and deactivates 
the antiapoptotic protein kinase B pathway, a key driver of radiotherapy resistance.  The targeted 
effect on ENOX2 has the potential to limit toxicity to non-cancer cells, which preferentially 
express ENOX1.  Previous studies have demonstrated improved radiation sensitivity in prostate 
cancer with flavonoid derivatives.  Early studies of intravenous and oral formulations of 
idronoxil were hampered by limited bioavailability.  The Sponsor has sought to address the 
problem of extensive drug metabolism through the development of a rectal suppository dosage 
form.  With blood draining from the distal part of the rectum directly into the inferior vena cava, 
first pass liver metabolism can be avoided.  In the case of a diphenolic drug such as idronoxil, the 
bioavailability is augmented by the rectal mucosa being known to be devoid of transferase 
activity and therefore the phase II metabolism is significantly reduced.  These two aspects 
combined are the basis for the rationale that idronoxil delivered via the rectum is subjected to 
less phase I and phase II metabolism than that observed for orally administered idronoxil.  
NOX66 is a suppository dosage form of idronoxil in a proprietary fatty base containing a 
surfactant.  This formulation is novel in that a lipophilic active ingredient is dispersed in a 
lipophilic suppository base – compared with traditional suppository formulations whereby a 
hydrophilic base would normally be utilized.  Moreover, this suppository dosage form provides a 
slow and sustained release of idronoxil comparable to an intravenous infusion. 


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The first clinical study with NOX66 (NOX66-001A) was a Phase 1a/1b study in which NOX66 
was evaluated both as a monotherapy and in combination with carboplatin, in patients with 
refractory solid tumors.  Two breast cancer (BC) patients and one ovarian cancer patient enrolled 
in this study had reductions in target lesions size with one BC patient showing target lesion 
disappearance (as per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1.) at the end 
of the study. 
The NOX66-002A study evaluated NOX66 in combination with external beam radiotherapy 
(EBRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).  Twenty-five 
patients received radiation therapy and 7 to 16 days of NOX66 treatment in this study. 
The overall radiological assessment according to RECIST v1.1 at 3 months for 19 evaluable 
patients resulted in 17 patients with disease control (1 patient in the 800 mg and 2 patients in 
1200 mg dose cohort with partial response [PR], 14 patients with stable disease [SD]) and 
2 patients, 1 each in the 400 mg and 800 mg cohorts, respectively, with disease progression.  At 
6 months and of the 15 evaluable patients, 1 continued to have PR and 60% continued to have 
SD.  There were two changes among the patients with PR in the 1200 mg cohort, with 1 patient 
not evaluable due to withdrawal and the other patient progressing to disease progression by 
RECIST v1.1 criteria while maintaining a prostate-specific antigen (PSA; 69%) and pain 
response (69% in overall pain score). 
The overall disease control rate (DCR) at 6 months was 66.6% (10/15), with 9 patients having 
SD and 1 patient PR.  The patient with PR also had a PSA decrease of 86% and a symptom 
control response of being 100% pain-free.  A clinical meaningful response in a non-irradiated 
lesion was also observed in the same patient, with a reduction in tumor size of 26.1% from 
baseline at 3 months and a continued decline to 49.3% at 6 months (abscopal response).  Four of 
15 patients had an abscopal response in non-irradiated lesions that were outside of the radiation 
field. 
NOX66 is designed to improve drug delivery and exposure of idronoxil to tumor cells.  This 
Phase 1b/Phase 2a clinical study will explore higher doses of NOX66 and expand the experience 
of NOX66 in men with mCRPC and patients with other solid tumors to determine the 
recommended Phase 2 dose (RP2D) and provide preliminary evidence on overall tumor response 
rate, survival, symptomatic relief of pain as well as other symptoms of this disease, and effects 
on PSA levels (for mCRPC patients only). 


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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Objectives and Endpoints 
Part 1 (Dose Escalation): 
The primary objective for Part 1 will be determined 
based on the count of DLTs. 
To determine the MTD and RP2D of 
NOX66 in combination with low-dose 
EBRT in patients with any solid tumor 
• 
MTD is defined as the dose level at which no 
more than 1 patient out of 6 experiences a DLT 
at the end of Cycle 1. 
• 
RP2D is the highest dose administered at which 
no more than 1 patient out of 6 experiences a 
DLT at the end of Cycle 1 and the dosage form, 
including the dosing frequency, is acceptable to 
patients. 
Part 2 (Dose Expansion): 
 
Arm 1: To evaluate the effect of NOX66 
on PSA response in patients with 
mCRPC. 
 
Arm 2: To evaluate the effect of NOX66 
on DCR in patients with BC and 
NSCLC. 
• 
PSA response is defined as the proportion of 
patients with a reduction in PSA in plasma 
(ng/mL) of ≥ 30% from baseline at the end of 
Cycles 3 and 6. 
• 
DCR is measured by the percentage of patients 
with a best overall confirmed response of CR or 
PR and SD. 
Secondary Objectives and Endpoints 
Characterize the safety and tolerability 
of NOX66 
Safety and tolerability of NOX66 as determined by 
AEs, TEAEs, clinical laboratory evaluations, vital 
signs, 12-lead ECG and physical examinations. 
Evaluate the safety and tolerability of 
both doses of EBRT 
Safety and tolerability of both doses of EBRT as 
determined by AEs, TEAEs, clinical laboratory 
evaluations, vital signs, 12-lead ECG and physical 
examinations. 
Evaluate the exposure of idronoxil 
Concentration of idronoxil and selected metabolites 
in plasma and derived PK parameters, including but 
not limited to: Cmax, Tmax, AUC(0-t), AUC(0-6), 
AUC(0-12), AUC(0-inf), Cmin and t½, as data permit. 


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Objectives 
Endpoints 
Evaluate the preliminary clinical 
efficacy of NOX66 plus low-dose 
EBRT in patients with mCRPC and 
other solid tumors 
Preliminary clinical efficacy as determined by: 
• 
Change from baseline in PSA (mCRPC only) at 
any time point. 
• 
Overall response rate assessed by RECIST v1.1 
criteria (all tumor types) and PCWG-3 criteria 
(mCRPC). 
• 
Duration of response (for patients with 
measurable disease). 
• 
Change from baseline ECOG scores. 
• 
Change from baseline in tumor size and number. 
• 
PFS and OS. 
Explore the effects of NOX66 on pain 
and other cancer-related signs and 
symptoms 
Effects on pain and other cancer-related signs and 
symptoms as determined by: 
• 
Change from baseline in pain scores based on 
the BPI-SF questionnaire. 
• 
SREs and SSEs. 
• 
Change of dose and frequency of morphine 
administration and analgesic use. 
Evaluate the QoL using PRO 
questionnaires 
QoL as assessed by: 
• 
Change from baseline in PEQ. 
• 
Change from baseline in EORTC-QLQ-C30. 
• 
Change from baseline in FACT-P (mCRPC 
only). 
Exploratory Objectives and Endpoints 
Characterize the relationship between 
pharmacodynamic biomarkers and 
idronoxil plasma concentrations (if a 
meaningful change is observed) 
• Change in biomarkers (cytokines, chemokines 
and ctDNA) from baseline. 
• Change in lipid profile from baseline. 
AE = adverse event; BC = breast cancer; BPI-SF = Brief Pain Inventory – Short Form; CR = complete response; 
ctDNA = circulatory tumor deoxyribonucleic acid; DCR = disease control rate; DLT = dose-limiting toxicity; 
EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
for Cancer Patients; FACT-P: Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic 
castration-resistant prostate cancer; MTD = maximum tolerated dose; NSCLC = non-small-cell lung cancer; 
OS =  overall survival; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; PRO = Patient Reported 
Outcome; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid 
Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; SRE = skeletal-related events; 
SSE = symptomatic skeletal events; TEAE = treatment-emergent adverse event 
 


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Overall Design: 
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, 
RP2D, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil 
when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) 
and patients with mCRPC, BC and non-small-cell lung cancer (NSCLC) (Part 2) who are eligible 
for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for the 
prevention of symptoms).  The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 
(dose expansion).  The study design allows an exploration of different doses of NOX66 (800 mg, 
1200 mg, 1600 mg and 2400 mg) with safety monitoring to ensure the safety of the patients.  A 
Safety Steering Committee (SSC) will review available safety data after the first cycle (21 days) 
of each dose cohort of NOX66 in Part 1 to determine the maximum tolerated dose (MTD)/RP2D. 
In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day 
cycle.  From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest 
period on a 14-day cycle.  Patients will continue to receive NOX66 on a cyclical basis until 
disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer 
therapy, withdrawal of the patient by the Investigator or termination of the study by the Sponsor. 
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gray (Gy) as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be administered on Day 2 of Cycle 1 and the remaining dose 
fractions will be given between Day 3 and Day 11.  The choice of one of the EBRT 
dose/fractions stated above will be at the discretion of the Investigator and will be determined by 
the clinical requirements of the patient.  EBRT will be administered according to the institutional 
protocol. 
The expected study duration for each patient from initial administration of NOX66 until the last 
study visit is determined by the number of treatment cycles each patient receives plus the 
follow-up period, which is from the last dose of NOX66 until death or the patient is lost to 
follow-up. 


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The study will finish when the last patient enrolled in Part 2 completes 6 months of treatment 
and all patients receiving study drug at that time will be switched to the NOX66 compassionate 
access program.  Those patients on the compassionate access program will continue to receive 
NOX66 treatment until disease progression or unacceptable toxicity.  These patients will be 
followed until death, or the patient is lost to follow-up. 
There will be a Screening period of up to 27 days (Days -28 to -2).  Each patient will attend the 
study center on Day -1 of Cycle 1 for eligibility assessments and on all PK days 
(Cycle 1: Days 1, 2, 6, 14 and 15; Cycles 2 and 3: Days 1 and 8).  Patients in Part 1 may require 
an overnight stay on Day 1 of Cycle 1.  On Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3, the NOX66 morning administration will occur at the study center under medical 
supervision.  During these days blood samples for PK analysis will be collected as per the 
schedule mentioned in Table 1-3.  In addition to PK samples, patients will be monitored for 
cardiac effects using 12-lead electrocardiograms (ECGs) (Table 1-2).  NOX66 will be 
self-administered by the patients or administered by their care giver at home on all other dosing 
days as well as the evening doses of NOX66 on PK days (Cycle 1: Days 2, 6 and 14; Cycles 2 
and 3: Day 1).  The evening dose of Day 1 of Cycle 1 (in Part 1 only) will be administered at the 
clinical unit.  Patients or care givers should always wear gloves when handling and/or during 
administration of NOX66.  The use of a small amount of water-soluble lubricant is advised 
before rectal administration.  Further administration and handling instructions are provided in the 
“Instructions for Administration of NOX66 Suppositories” document.  Patients will also attend 
the study center for EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively) on 
Days 2 to 11 of Cycle 1 depending on the number of fractions administered.  From Cycle 2 
onwards only NOX66 will be administered for 7 days followed by a 7-day rest period (as 
indicated above).  Patients with mCRPC may also receive androgen deprivation therapy as 
maintenance therapy and patients with BC may receive background hormonal therapy during this 
study.  No other anticancer therapy will be allowed during the study.  Patients will have an 
End of Treatment (EOT) Visit within 7 to 10 days after the last dose of study drug.  If a patient 
discontinues the study early (Early Discontinuation [ED]), the patient will have an ED Visit 
within 7 to 10 days after the last dose of study drug. 
Patients in both study parts will be followed up by phone for adverse events (AEs)/serious 
adverse events (SAEs) for 30 days after the last dose of study drug or until resolution or 
stabilization of ongoing AEs/SAEs deemed at least possibly related to the study drug, whichever 
is longer.  All patients (including patients who discontinued the study early for reasons other than 
disease progression) will be followed up approximately every 12 weeks (± 2 weeks) after 
completion of the treatment period for disease progression up to 12 months, and for safety until 
death or the patient is lost to follow-up.  Patients who discontinued the study early for reasons 


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other than disease progression will attend the clinical unit for the follow-up visits.  Patients will 
receive the study drug until disease progression, unacceptable toxicity, withdrawal of consent, 
initiation of new anticancer therapy, withdrawal of the patient by the Investigator or termination 
of the study by the Sponsor.  Patients who discontinued from the study for reasons other than 
progression will have tumor imaging and disease response assessments performed for up to 
12 months after the last dose of study drug until disease progression, withdrawal of consent, 
initiation of new anticancer therapy, the patient is lost to follow-up or death, whichever comes 
first. 
The study schemes are provided in Figure 1–1 (Part 1) and Figure 1–2 (Part 2), and the Schedule 
of Activities is provided in Table 1-1 (Parts 1 and 2). 
Part 1 (Dose Escalation) 
Approximately 30 patients with any solid tumor who require low-dose EBRT will be enrolled 
sequentially to the four planned NOX66 dose groups (Dose Cohort 1: 800 mg [3 to 6 patients]; 
Dose Cohort 2: 1200 mg; Dose Cohort 3: 1600 mg; Dose Cohort 4: 2400 mg [3 to 8 patients in 
each of Dose Cohorts 2 to 4]; total daily dose administered twice a day [BID]).  At least 
2 patients enrolled in Dose Cohorts 2 to 4 must have mCRPC. 
The proposed dose regimen for Part 1 is given in the table below.  No intra-subject dose 
escalation is allowed. 
Proposed Doses for NOX66 (Part 1) 
 
Dose Cohort 
1 
2 
3 
4 
Total daily dose 
800 mg 
1200 mg 
1600 mg 
2400 mg 
Dosing regimen 
400 mg BID 
600 mg BID 
800 mg BID 
1200 mg BID 
Number of suppositories per 
day 
2 × 400 mg 
2 × 600 mg 
4 × 400 mg 
4 × 600 mg 
BID = twice daily 
 
All patients will be closely monitored for any dose-limiting toxicities (DLTs) up to Day 21 of 
Cycle 1. 
Dose escalation will be based on an adapted “3+3” design, where dose cohorts will be expanded 
for up to 6 patients (Dose Cohort 1) in the event of DLT or up to 8 patients (Dose Cohorts 2 to 4) 
to allow for robust estimation of PK parameters after being deemed “safe” based on the 
traditional “3+3” design. 


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At each dose level, 3 patients will initially be treated with NOX66. 
• 
If none of the first 3 patients enrolled in Cohort 1 experience a DLT during the first treatment 
cycle, the dose will be escalated to the next level. 
• 
If none of the first 3 patients experience a DLT during the first treatment cycle of Cohorts 2 
to 4, then the dose level will be deemed “safe” and up to 5 additional patients will be enrolled 
to the current dose level for estimation of PK parameters.  At the same time (with the 
exception of Cohort 4), the next dose level will be initiated and the first 3 patients will be 
enrolled to the escalated dose. 
• 
If 1/3 patients experience a DLT, an additional 3 patients will be enrolled.  If 1/6 patients 
experience a DLT then this dose level will be deemed “safe” and, for Cohorts 2 to 4, 2 more 
patients may be enrolled for estimation of PK parameters.  At the same time, the next dose 
level will be initiated and the first 3 patients will be enrolled to the escalated dose. 
• 
If > 1/3 or > 1/6 patients experience a DLT, then dose escalation will be halted, and the 
previous dose will be declared as the MTD. 
If the 1200 mg dose is not tolerable (i.e., 2 or more patients with DLTs), an additional 3 patients 
will be enrolled in the 800 mg dose cohort in order to declare 800 mg as the MTD (if no more 
than 1/6 patients experience a DLT). 
If no DLT is observed at 2400 mg (Dose Cohort 4), dose escalation will be stopped.  The 
proposed highest dose level (2400 mg) will be declared the RP2D. 
There will be a temporary halt for enrollment after the first 3 patients are enrolled in each cohort 
until the SSC clears that the dose level is safe to continue the dose escalation. 
During the SSC meeting for NOX66 dose escalation decision, the safety and tolerability of both 
EBRT doses (8 Gy and 20/25 Gy) will also be evaluated. 
DLT monitoring will be applicable for all patients enrolled in each cohort, including patients 
enrolled for the purpose of PK analysis; as well as the decision rule for the additional PK patients 
(i.e., stopping dose escalation). 
Part 2 (Dose Expansion) 
Part 2 will be expanded to enroll additional patients with mCRPC (Arm 1), BC and NSCLC 
(Arm 2).  All patients will be treated with NOX66 RP2D along with low-dose EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively).  Approximately 40 patients in Arm 1 
and 24 to 30 patients in Arm 2 will be enrolled. 


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Eligibility Criteria: 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent 
1. Patient is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form and in this protocol. 
Type of Patient and Disease Characteristics 
2. Patient has a minimum life expectancy of 6 months. 
3. Patient is 18 years or older at the time of signing the informed consent. 
4. Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid 
tumors. 
5. Confirmed metastatic disease by imaging (e.g., bone scans, X-rays, ultrasound, computerized 
tomography, magnetic resonance imaging). 
6. Documented disease progression (e.g., based on radiographic imaging, PSA or other clinical 
parameters) following first or later lines of anticancer systemic treatment. 
7. Patient is eligible for low-dose EBRT for at least one lesion. 
8. Patients with prior RT are eligible, only if there is no potential for field overlap between the 
prior RT and the planned RT. 
9. For patients with BC or NSCLC: Patient must have at least one measurable lesion as per 
RECIST v1.1 (in Part 2 only). 
10. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
11. Adequate bone marrow function defined as: 
• 
Absolute neutrophil count ≥ 1.5 × 109/L. 
• 
Platelet count ≥ 100 × 109/L. 
• 
Hemoglobin ≥ 9.0 g/dL (with or without transfusion). 
12. Adequate renal function defined as: 
• 
Creatinine clearance as measured by the Cockcroft-Gault equation > 30 mL/min. 


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13. Adequate liver function defined as: 
• 
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN; patients with confirmed 
Gilbert’s syndrome may be included in the study). 
• 
Aspartate aminotransferase/alanine aminotransferase ≤ 2.5 × ULN (or ≤ 5 × ULN in 
patients with liver metastasis).  Elevated alkaline phosphatase is not exclusionary if due 
to the presence of bone metastasis and liver function is otherwise considered adequate in 
the Investigator’s judgement. 
Metastatic Castration-resistant Prostate Cancer 
14. Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained 
throughout the duration of the study. 
15. Patient has evidence of symptomatic and/or progressive disease.  Progressive disease is 
defined as any one of the following: 
• 
Radiographic disease progression in soft tissue (nodule or visceral metastasis) and/or 
bone with or without PSA progression.  Objective evidence of increase in radiographic 
lesions or the appearance of 2 or more new lesions 
• 
Prostate-specific antigen progression: At least 3 consecutive rising PSA levels (≥ 2 to 
5 ng/mL) separated by at least 1 week, with castrate levels of testosterone. 
Breast Cancer Patients 
16. Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen 
receptors alone).  Breast cancer patients are allowed to be on background hormonal 
treatment. 
Contraception 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
NOTE: The reliability of sexual abstinence for male or female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Male Patients: 
17. Patient must have had a vasectomy or must agree to use a highly effective contraception as 
detailed in Section 10.4 of this protocol during the treatment period and for at least 3 months 
after the last dose of study drug and refrain from donating sperm during this period. 


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Female Patients: 
18. A female patient is eligible to participate if she is not pregnant (see Section 10.4), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4. 
OR 
• 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 and not to 
donate ova during the treatment period and for at least 3 months after the last dose of 
study drug. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Patient has tumor involvement of the central nervous system. 
2. Impaired cardiac functioning or clinically significant cardiac disease, including the 
following: 
• 
Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study 
drug. 
• 
Corrected QT interval using Fridericia’s formula > 470 msec on screening ECG (average 
of triplicate measurement will be used). 
• 
Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
NOTE: Patients with a history of coronary artery disease, revascularization and/or stable 
coronary artery disease are not excluded. 
3. Uncontrolled hypertension despite two concomitant antihypertensive therapies, defined as 
supine systolic blood pressure ≥ 150 mmHg or diastolic blood pressure > 100 mmHg based 
on a mean of three measurements at approximately 2-minute intervals. 
4. Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis. 
5. Patients for whom administration of the suppositories are likely to cause pain or difficulties 
in absorption (e.g., inflamed hemorrhoids, fissures or lesions of the anus or rectum). 
6. Patients with fecal impaction or uncontrolled irritable bowel disease. 
7. Patients with inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) will be 
excluded, even if the condition is well controlled. 


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8. Active or chronic infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C.  Screening of patients with serology testing for these viruses is not required.  
However, patients who have a past history of viral hepatitis or in whom there is a current 
suspicion of viral hepatitis will have serology testing for hepatitis B and hepatitis C 
performed to determine whether there is any current evidence of ongoing infection with these 
viruses.  Patients considered to be at risk for HIV infection should have HIV testing 
performed.  If the test result is negative, the patient will be allowed to participate in the study. 
NOTE: Patients with chronic HIV infection, on ongoing treatment with anti-viral 
medications, who have an undetectable viral load are not considered to be infectious and can 
be included in this study. 
9. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory 
finding that, in the Investigator’s opinion, gives reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, render the patient at high risk from treatment complications or interferes with 
obtaining informed consent. 
10. Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard 
therapy will be excluded. 
11. Major surgery within 4 weeks or minor surgery or biopsy within 1 week of the first dose 
administration. 
12. Patients who have had RT to the region of the rectum or will require RT to the region of the 
rectum during the trial.  
NOTE: Metastatic castration-resistant prostate cancer [mCRPC] patients who have received 
prior prostate or prostate fossa radiation and radiation to nearby lymph nodes, where the 
rectum is not the target, can be included in this study. 
Prior/Concomitant Therapy 
13. Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal 
medications within 14 days before the first dose administration.  Infections (e.g., urinary tract 
infection) controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per 
institutional guidelines are acceptable. 
14. Receiving or having received anticancer treatment within the following period prior to the 
first dose administration: 
• 
Cytotoxic treatment: 3 weeks. 


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• 
Non-cytotoxic drugs, including small molecule investigational products: 3 weeks or 
5 terminal half-lives from plasma (whichever is the longest). 
• 
Biological products including investigational immune-oncology agents: 4 weeks. 
• 
Radiation with a limited field for palliation: 4 weeks. 
• 
Radiation to > 30% of the bone marrow: 4 weeks. 
• 
Lung radiation: 60 days. 
15. Patient has received corticosteroids at a dose of > 10 mg prednisone/day or equivalent for 
any reason within 4 weeks prior to receiving the first dose administration. 
16. History of hypersensitivity to active or inactive excipients of study drug or drugs with a 
similar chemical structure or class to the study drug. 
Other Exclusions 
17. Patient is not willing to use suppositories. 
18. Judgement by the Investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 
19. Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prior to Screening or 
enrollment, or has clinical signs and symptoms consistent with SARS-CoV-2 infection; 
e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive SARS-CoV-2 test result within 
2 weeks prior to Screening.  Patients who had symptomatic coronavirus disease 2019 
(COVID-19) less than 1 month prior to Screening will be excluded.  If a patient has had a 
severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically 
ventilated) within 4 weeks of Screening, or have any sequelae of infection or ongoing 
infection, the patient will also be excluded.  If the patient has had recent (within previous 
14 days) exposure to someone who has COVID-19 symptoms, been in contact with someone 
who has tested positive for COVID-19 or visited a COVID-19 treatment facility, the patient 
may be re-evaluated for participation in the study after undergoing an isolation period of at 
least 10 days and having a negative SARS-CoV-2 RT-PCR test prior to enrollment. 
Disclosure Statement:  
This is an open-label, multicenter, sequential 2-part treatment study (Part 1 and Part 2). 
Number of Arms: 
The study will include 4 dose cohorts (Part 1) and 2 treatment arms (Part 2). 


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Number of Patients: 
The sample sizes selected for this study are as follows: 
• 
Part 1 (Dose Escalation): Up to 30 patients will be enrolled in Part 1, in cohorts of 3 to 
6 patients (Dose Cohort 1) or 3 to 8 patients (Dose Cohorts 2 to 4) at each specified dose. 
• 
Part 2 (Dose Expansion): A total of 40 patients with mCRPC will be enrolled in Arm 1 and 
24 to 30 patients (12 to 15 patients per tumor type [BC and NSCLC]) will be enrolled in 
Arm 2. 
Dosing Groups and Duration: 
• 
Part 1: Eligible patients with any solid tumor will be enrolled in one of 4 dose cohorts: 
o Dose Cohort 1: 800 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on the number of fractions to be administered).  From Cycle 2 
onwards, 800 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 2: 1200 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1200 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 3: 1600 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1600 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 4: 2400 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
2400 mg NOX66 will be administered on Days 1 to 7. 
• 
Part 2: Eligible patients will be enrolled in 1 of 2 treatment arms: 
o Arm 1 – patients with mCRPC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 
to 11 of Cycle 1, depending on number of fractions to be administered).  From Cycle 2 
onwards, RP2D NOX66 will be administered on Days 1 to 7. 
o Arm 2 – patients with BC and NSCLC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT 
(Days 2 to 11 of Cycle 1, depending on number of fractions to be administered).  From 
Cycle 2 onwards, RP2D NOX66 will be administered on Days 1 to 7. 
Patients will have a rest period (no NOX66 administration) on Days 15 to 21 of Cycle 1 and 
Days 8 to 14 of Cycle 2 onwards (Parts 1 and 2). 


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Study Assessments: 
Efficacy will be assessed by evaluating the change from baseline PSA for patients with mCRPC.  
For all patients, DCR (as measured by complete response [CR], PR and SD) will also be 
evaluated based on change from baseline imaging using RECIST v1.1 criteria.  Bone lesions will 
be evaluated using Prostate Cancer Working Group 3 (PCWG-3) criteria.  Other assessments to 
be performed during this study are ECOG scores, pain severity, and Patient Reported Outcomes.  
Efficacy will also be evaluated by examining skeletal-related events (SREs), symptomatic 
skeletal events (SSEs), progression-free survival (PFS), overall survival (OS), and objective 
response rate. 
Safety and tolerability of NOX66 and separately for both doses of EBRT (8 Gy or 20/25 Gy) will 
be determined by AEs, treatment-emergent adverse events (TEAEs), clinical laboratory 
evaluations, vital signs, 12-lead ECGs and physical examinations.  The study will also evaluate 
DLTs during Cycle 1 of Part 1. 
Plasma PK analysis for idronoxil and selected metabolites will be performed for Part 1 (all 
patients) and Part 2 (first 10 patients enrolled for each tumor type). 
Changes from baseline in the lipidomic profile, plasma levels of cytokines and chemokines (all 
sites), and circulatory tumor deoxyribonucleic acid (ctDNA; all patients participating at 
pre-selected sites only) will be assessed (Parts 1 and 2). 
Statistical Analyses: 
The main aims of the study are to assess the safety, tolerability, efficacy, PK and PD profiles of 
idronoxil (and selected metabolites) and EBRT in patients with prostate cancer and other solid 
tumors. 
Continuous data will be summarized using the number of patients (n), mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum.  Categorical data will be summarized 
using frequency tabulations (number and percentage of patients). 
Baseline will be defined as the last measurement obtained prior to the first administration of 
NOX66. 
Disposition of patients will be listed and summarized.  Patient demographics, baseline 
characteristics, concomitant medications and exposure to study drug will be listed and 
summarized for each study part by dose cohort (Part 1) or treatment arm (Part 2) using 
appropriate descriptive statistics. 


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Primary Endpoint Analyses 
The primary endpoint for Part 1 (dose escalation) is the number of DLTs, which will be used to 
estimate the MTD and select the RP2D.  This will be determined by the dose level at which no 
more than 1 out of 6 patients experiences a DLT during Cycle 1.  For assessment of DLTs, 
toxicities will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) v22.0 
or higher and graded according to National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0.  The number of DLTs experienced by a patient will be 
summarized by DLT type for each dose cohort and DLT events will be listed by patient.  The 
listing will include the description, severity and relationship of the events to study drug. 
The primary endpoint for Part 2 Arm 1 (mCRPC patients) is the proportion of patients who 
achieve ≥ 30% reduction in PSA from baseline at the end of Cycles 3 and 6.  Plasma levels of 
PSA will be collected on Day 1 of Cycles 1 to 5, every second cycle thereafter (i.e., Cycles 7, 9, 
11 etc.), at the EOT/ED Visit and at the 6-, 9- and 12 month Follow-up Visits for all patients 
including those that discontinued for any reason other than disease progression.  The number and 
proportions of patients with a ≥ 30% reduction in PSA levels from baseline to the end of 
Cycles 3 and 6 (primary endpoint) and change from baseline at any time point (secondary 
endpoint) will be presented for Treatment Arm 1 along with the corresponding exact 95% 
confidence interval (CI; Clopper-Pearson). 
The primary endpoint for Part 2 Arm 2 (BC and NSCLC patients) is DCR assessed by 
determining the percentage of patients with the best overall response of CR or PR at any time 
plus SD from the first dose administration until disease progression, death due to any cause or 
the start of new anticancer therapy, respectively.  RECIST v1.1 criteria will be applied to assess 
CR, PR and SD.  Disease control rate will be presented for Treatment Arm 2 along with the 
corresponding exact 95% CI (Clopper-Pearson).  Tumor imaging and disease response 
assessments will be performed for up to 12 months after the last dose of study drug until disease 
progression, withdrawal of consent, initiation of new anticancer therapy, the patient is lost to 
follow-up or death, whichever comes first. 


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Secondary Endpoint Analyses 
• 
Safety Analysis 
Safety profiles will be summarized by NOX66 dose cohort and separately by EBRT dose 
cohort (Part 1) or treatment arm and separately by EBRT dose cohort (Part 2) and will be 
based on the Safety Analysis Set.  Adverse events will be coded using the MedDRA v22.0 or 
higher and will be graded according to the NCI-CTCAE v5.0.  Treatment-emergent AEs are 
defined as those AEs that either start or worsen in severity on or after the date of first 
administration of study drug and on or before 30 days after the last dose of study drug.  
Treatment-emergent AEs will be summarized by severity grade and relationship to study 
drug.  Serious AEs, serious TEAEs and TEAEs leading to discontinuation of study drug or to 
death will be presented.  Changes in clinical laboratory values, vital signs, ECGs and 
physical examinations will be summarized over time. 
• 
Efficacy Analysis 
Efficacy analysis will be conducted for the patients enrolled to Part 1 and Part 2 of the study.  
Results will be summarized by dose cohort (Part 1) or treatment arm (Part 2).   
o PSA samples (patients with mCRPC) will be collected on Day 1 of Cycles 1 to 5, every 
second cycle thereafter (i.e., Cycles 7, 9, 11, etc.), at the EOT/ED Visit and at the 6-, 9- 
and 12-month Follow-up Visits for all patients including those that discontinued for any 
reason other than disease progression.  A PSA response will be considered as a PSA value 
reduction ≥ 30% from baseline at the end of Cycles 3 and 6.  A PSA reduction from 
baseline at any time point will also be assessed as a secondary objective. 
o Overall response rate, defined as the percentage of patients with CR and PR, will be 
assessed based on change from baseline imaging (RECIST v1.1 and PCWG-3 criteria for 
measurable or evaluable lesions).  The number and proportion of responders (CR and PR) 
will be presented along with the exact 95% CI (Clopper-Pearson) for the time points after 
Day 1.  Tumor imaging assessment will be continued as scheduled for the patients who 
are discontinued from the study for reasons other than disease progression.  The best 
overall response (CR, PR, SD or progression) will be summarized. 
o Change from baseline in ECOG, pain severity and pain interference with daily activities, 
and dose and frequency of morphine administration and analgesic use will be 
summarized over time.  The number and proportion of patients with a pain response 
(≥ 2-point reduction in pain severity and no additional opioid use) will be summarized 
over time along with the exact 95% CIs (Clopper-Pearson).  The number and proportion 
of patients with SREs and/or SSEs will be summarized at each time point and presented 
along with the exact 95% CI (Clopper-Pearson). 


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o Scale measures from the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire for Cancer Patients (EORTC-QLQ-C30), Brief pain 
inventory-short form (BPI-SF), Patient Experience Questionnaire (PEQ), and Functional 
Assessment of Cancer Therapy – Prostate (FACT-P; mCRPC patients only) will be 
summarized for all patients by dose at each visit as well as the change from baseline to 
each visit. 
o Survival functions will be computed for OS, PFS and PSA reduction/progression (for 
Part 2, Arm 1 only) using the Kaplan-Meier method.  Estimates of median survival times 
will be presented along with 2-sided 95% CIs.  The 25th and 75th percentiles and the range 
(minimum, maximum) will be presented as well. 
o Duration of response is defined as the time from the first documented overall response of 
CR, PR or SD to the first documented overall response of progressive disease.  This will 
be estimated using the Kaplan-Meier method.  Estimates of median survival times will be 
presented along with the two-sided 95% CI.  The 25th and 75th percentiles and range 
(minimum, maximum) will also be presented. 
• 
Pharmacokinetic Analysis: 
Plasma samples will be assayed for idronoxil and up to 7 selected metabolites by validated 
high-performance liquid chromatography and mass spectrometry methodology.  Individual 
plasma concentration-time data and plasma PK parameters will be summarized using 
descriptive statistics by treatment day and sampling time for idronoxil and the 7 detectable 
metabolites (GIS/SIG, IG, GI, IS, SI, SIS, and GIG).  Plasma PK parameters will be 
determined by noncompartmental analysis for idronoxil and selected metabolites and will be 
summarized by dose and treatment day. 
o The following PK parameters will be estimated for idronoxil and the selected metabolites 
following the morning dose on Days 1, 6 and 14 of Cycle 1, as data permit: Cmax, Cmin 
(predose), Tmax, AUC(0-t), AUC(0-6), AUC(0-12), AUC(0-inf) and t½. 
o Dose proportionality will be assessed for Cmax, AUC(0-t), AUC(0-inf), AUC(0-6), and 
AUC(0-12) on Days 1, 6 and 14 of Cycle 1 for the parent compound. 
o If data permits, accumulation ratios will be calculated for parent compound and selected 
metabolites for Cmax, Cmin, AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) for Days 6 and 14 
of Cycle 1 (e.g., Day 14/Day 1 and Day 6/Day 1) and Day 8 of Cycles 2 and 3. 
o The metabolite to parent ratios will be calculated (as data permit) for Days 1, 6 and 14 of 
Cycle 1, for AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) and for single time points on 
Day 1 of Cycles 2 and 3. 


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Concentration and PK parameter data will be listed, summarized and plotted. 
There are no formal PK parameters for concentration data from Cycles 2 and 3 because these 
are single time points.  However, metabolite to parent ratios will be explored. 
Exploratory analyses of the relationship between plasma concentrations of parent drug and 
selected metabolites and/or PK parameters and AEs or PD biomarkers may be assessed by 
graphical methods and special summary tables.  Exposure-response relationship may also be 
explored. 
• 
Pharmacodynamic Biomarker Analysis: 
Plasma levels of cytokines and chemokines will be evaluated as part of the PD biomarker 
analysis.  Using the plasma samples, analysis will be performed for ctDNA and lipidomic 
profiling (capturing over 300 lipid species as determined by liquid chromatography-tandem 
mass spectrometry).  Absolute and change from baseline results of biomarker analysis will be 
summarized descriptively and also presented on a plot. 
All statistical analysis will be performed using Statistical Analysis Software® Version 9.3 or 
higher.  Further details regarding statistical analyses will be provided in the statistical analysis 
plan. 
Data Monitoring Committee:  
A Data Monitoring Committee will not be appointed.  Patient safety and scientific integrity of 
the study will be monitored by the SSC. 


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1.2 Schema 
Figure 1–1: 
Study Design: Part 1 
 
 
 
 
TREATMENT PERIOD* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1: Days 1 to 14 
 
NOX66 
• 
Dose Cohort 1 800 mg 
NOX66† 
• 
Dose Cohort 2: 1200 mg 
NOX66 
• 
Dose Cohort 3: 1600 mg 
NOX66 
• 
Dose Cohort 4: 2400 mg 
NOX66 
(Up to 6 patients for Dose 
Cohort 1 and up to 8 patients for 
Dose Cohorts 2 to 4) 
 
Low-dose EBRT (Days 2 to11, 
depending on number of fractions to be 
administered; EBRT must start on Day 2) 
 
Cycle 1: Days 15 to 
21 
 
 
 
 
Rest Period 
 
 
 
 
 
 
Screening 
 
 
 
 
 
Days -28 
to -2 
Eligibility 
assessment 
confirmation 
(Cycle 1 
only) 
 
 
Day -1 
 
EOT/ED 
 
 
 
 
 
7-10 days 
after last 
dose 
Safety FU 
 
 
 
 
 
Up to 
30 days after 
last dose 
FU 
 
 
 
 
 
Every 
12 weeks 
(± 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 onwards: Days 1 to 7 
 
NOX66 
• 
Dose Cohort 1 800 mg 
NOX66† 
• 
Dose Cohort 2: 1200 mg 
NOX66 
• 
Dose Cohort 3: 1600 mg 
NOX66 
• 
Dose Cohort 4: 2400 mg 
NOX66 
 
 
Cycle 2 onwards: 
Days 8 to 14 
 
 
 
Rest Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Dose Escalation between Dose Cohorts 1 to 4 
 
 
800 mg NOX66 
Enroll 3 patients 
 
 
 
0 DLT 
 
1 DLT 
2 DLT 
 
Escalate to 1200 mg NOX66 
(Enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
Lower dose may be used 
   0 DLT 
1 DLT 
 
 
 
 
 
Escalate to 1600 mg NOX66 
(enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
800 mg NOX66 
 
   0 DLT 
1 DLT 
 
 
 
 
 
Escalate to 2400 mg NOX66 
(Enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
1200 mg NOX66 
 
   0 DLT 
1 DLT 
 
 
 
 
 
Enroll 3 more patients 
 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
1600 mg NOX66 
  0 / 1 DLT 
2 DLT 
 
 
 
MTD 
2400 mg NOX66 
 
 
 
 
 
DLT = dose-limiting toxicity; EBRT = external beam radiotherapy; ED = early discontinuation; EOT = end of treatment; FU = Follow-up Visit; 
MTD = maximum tolerated dose 
See Section 4.1.1 and Section 7.1.2.2 for details on assessment of DLTs. 
* NOTE: Patients will receive the study drug until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, withdrawal 
of the patient by the Investigator or termination of the study by the Sponsor. 


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† Only 3 patients will be enrolled in Dose Cohort 1 (800 mg NOX66), unless there is a DLT.  If a DLT occurs, up to a maximum of 3 additional patients may be 
enrolled.  Additional patients will not be enrolled in Dose Cohort 1 for PK analysis. 
Patients who are considered evaluable for dose escalation review are 1) patients who have not experienced a DLT and has received at least 80% of the planned 
daily dose and completed all safety evaluations; 2) patients who developed DLT during the 21-day treatment cycle (Cycle 1).  For each dose cohort, at least 
3 evaluable patients are required for DLT evaluation and to make a decision on dose escalation. 
End of Treatment (EOT) Visit occurs 7 to 10 days after the last dose of study drug.  If patients discontinue the study early (Early Discontinuation [ED]), they will 
have an ED Visit within 7 to 10 days after the last dose of study drug. 
Once a patient completes or discontinues study drug, he/she will be followed up every 12 weeks (± 2 weeks) after the last dose of study drug for disease 
progression up to 12 months, and for safety until death or the patient is lost to follow-up. 
 


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Figure 1–2: 
Study Design: Part 2 
 
 
 
 
TREATMENT PERIOD* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1: Days 1 to 14 
 
NOX66 RP2D: Days 1 to 14 
 
Low-dose EBRT (Days 2 to 11, 
depending on number of fractions to be 
administered; EBRT must start on Day 2) 
 
Cycle 1: Days 15 to 
21 
 
 
 
 
Rest Period 
 
 
 
 
 
 
Screening 
 
 
 
 
 
Days -28 
to -2 
Eligibility 
assessment 
confirmation 
(Cycle 1 
only) 
 
 
Day -1 
 
EOT/ED 
 
 
 
 
 
7-10 days 
after last 
dose 
Safety FU 
 
 
 
 
 
Up to 
30 days after 
last dose 
FU 
 
 
 
 
 
Every 
12 weeks 
(± 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 onwards: Days 1 to 7 
 
NOX66 RP2D: Days 1 to 7 
 
Cycle 2 onwards: 
Days 8 to 14 
 
 
 
Rest Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BC = breast cancer; EBRT = external beam radiotherapy; ED = early discontinuation; EOT = end of treatment; FU = Follow-up Visit; mCRPC = metastatic 
castration-resistant prostate cancer; NSCLC = non-small-cell lung cancer 
Patient population: 
• 
Arm 1: mCRPC patients only (40 patients) 
• 
Arm 2: Patients with BC and NSCLC (24 to 30 patients [12 – 15 patients per tumor type]) 
End of Treatment (EOT) Visit occurs 7 to 10 days after the last dose of study drug.  If patients discontinue the study early (Early Discontinuation [ED]), they will 
have an ED Visit within 7 to 10 days after the last dose of study drug. 
Once a patient completes or discontinues study drug, he/she will be followed up every 12 weeks (± 2 weeks) after the last dose of study drug for disease 
progression up to 12 months, and for safety until death or the patient is lost to follow-up. 
* NOTE: Patients will receive the study drug until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, withdrawal 
of the patient by the Investigator or termination of the study by the Sponsor. 


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1.3 Schedule of Activities 
Table 1-1 
Schedule of Activities (SoA) – Part 1 and Part 2 
Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Informed consent c 
X 
 
 
 
 
 
 
In-house stay (optional) 
 
 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Patient Diary d 
 
 
X 
X 
X 
X 
 
Phone call e 
X 
X 
X 
X 
X 
X 
X 
Routine Clinical Procedures 
Demographics 
X 
 
 
 
 
 
 
Medical history (including any available historical 
genetic assays conducted to identify genetic variations 
[all patients] and Gleason score for mCRPC patients 
only) f 
X 
X 
 
 
 
 
 
Physical examination g 
X 
 
X 
 
 
 
 
Height and weight g 
X 
 
 
 
 
 
 
Vital signs h 
X 
 
X 
X 
 
X 
 
ECG i 
X 
 
X 
X 
 
X 
 
Prior and concomitant medications j 
X 
X 
X 
X 
 
X 
 


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Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Routine Safety Measure 
Urinalysis k 
X 
 
X 
X 
 
X 
 
Hematology k, l 
X 
 
X 
X 
 
X 
 
Clinical chemistry k, m 
X 
 
X 
X 
 
X 
 
Coagulation k, n 
X 
 
X 
X 
 
X 
 
Testosterone (mCRPC) o 
X 
 
X 
 
 
 
 
Serology screen p 
X 
 
 
 
 
 
 
SARS-CoV-2 screen (optional; at Investigator’s 
discretion) q 
X 
 
 
 
 
 
 
FSH testing r 
X 
 
 
 
 
 
 
Pregnancy test s 
X 
 
X 
 
 
 
 
Adverse event t 
X 
X 
X 
X 
 
X 
 
Efficacy Measurements 
PSA u 
X 
 
X 
 
 
 
 
Tumor imaging (RECIST v1.1) CT/MRI v 
X 
 
 
 
 
 
 
Bone scan (PCWG-3) v 
X 
 
 
 
 
 
 
SRE and SSE evaluation 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
 
X 
 
 
 
 
EORTC-QLQ-C30 w 
X 
 
 
 
 
 
 
BPI-SF questionnaire w 
X 
 
 
 
 
 
 
FACT-P (mCRPC patients only) w 
X 
 
 
 
 
 
 
PEQ x 
 
 
 
X 
 
 
 
Survival status y 
 
 
 
 
 
 
 
Pharmacokinetic Measurement 
Blood sample for PK z 
 
 
X 
X 
 
X 
X 


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Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Pharmacodynamic Biomarker Assessment 
Blood sample for biomarkers aa 
X 
 
X 
 
 
 
X z 
Archived tissue collection if available (Optional) bb 
X 
 
 
 
 
 
 
Fresh tissue biopsy after Cycle 3 treatment (Optional) 
bb 
 
 
 
 
 
 
 
Treatment Administration 
NOX66 cc 
 
 
X 
X 
X 
X 
 
EBRT (1-10 days) dd 
 
 
 
X 
 
 
 
 
 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-up b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Informed consent c 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Diary d 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Phone call e 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Routine Clinical Procedures 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
any available historical 
genetic assays conducted to 
identify genetic variations 
[all patients] and Gleason 
score for mCRPC patients 
only) f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination g 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Weight g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs h 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
ECG i 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Prior and concomitant 
medications j 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-up b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Routine Safety Measure 
Urinalysis k 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Hematology k, l 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Clinical chemistry k, m 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Coagulation k, n 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Testosterone (mCRPC) o 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Serology screen p 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 screen 
(optional; at Investigator’s 
discretion) q 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH testing r 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test s 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Adverse event t 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Efficacy Measurements 
PSA u 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Tumor imaging (RECIST 
v1.1) CT/MRI v 
 
 
 
 
 
 
X 
 
 
 
X b 
 
X 
Bone scan (PCWG-3) v 
 
 
 
 
 
 
X 
 
 
 
X b 
 
X 
SRE and SSE evaluation 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
ECOG performance status 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
EORTC-QLQ-C30 w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
BPI-SF questionnaire w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
FACT-P (mCRPC patients 
only) w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
PEQ x 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Survival status y 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-up b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Pharmacokinetic Measurement 
Blood sample for PK z 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Pharmacodynamic Biomarker Assessment 
Blood sample for 
biomarkers aa 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Archived tissue collection if 
available (Optional) bb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tissue biopsy after 
Cycle 3 treatment 
(Optional) bb 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment Administration 
NOX66 cc 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
EBRT (1-10 days) dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; BPI-SF = Brief Pain Inventory – Short Form; C1D1 = Cycle 1, Day 1; COVID-19 – coronavirus disease 2019; CT = computerized 
tomography; d = day(s); EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ED = Early 
Discontinuation; EORTC-QLQ-C30 = Quality of life Questionnaire for Cancer Patients; EOT = End of Treatment; FACT-P: Functional Assessment of Cancer 
Therapy – Prostate; FSH = follicle-stimulating hormone; Gy = Gray; mCRPC = metastatic castration-resistant prostate cancer; MRI = magnetic resonance 
imaging; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; PK = pharmacokinetics; PRO = Patient Reported Outcome; 
PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; SRE = skeletal-related events; SSE = symptomatic skeletal events; WBC = white blood cell; WOCBP = women of childbearing 
potential 


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† Patients will receive the study drug from Cycle 1 Day 1 and may continue to receive the study drug until disease progression, unacceptable toxicity, withdrawal 
of consent, start of new anticancer therapy, withdrawal of the patient by the Investigator or termination of the study by the Sponsor. 
‡ From Cycle 3 onwards, study drug for 2 cycles will be dispensed every second cycle (i.e., Cycles 5, 7, 9, 11 etc.).  From Cycle 5 onwards, on-site visits will 
occur on a 28-day (4 weekly) basis, i.e., patients will visit the clinical unit every second cycle.  After Cycle 5, the next on-site visit will therefore be Cycle 7, 
followed by Cycle 9, etc. until the patient completes the study treatment period or discontinues from the study, whichever comes first. 
§ The procedures listed and schedule followed for Cycle 4 will be assessed at all cycles without an on-site visit (unless otherwise specified). 
* The procedures detailed at Cycle 5 Day 1 will be performed for all subsequent on-site visits (unless otherwise specified).  Patients will continue NOX66 
administration in each cycle from Day 1 until Day 7 followed by a 7-day rest period (Days 8 to 14). 
It is important that PK sampling occurs as close as possible to the scheduled time.  In order to achieve this, other assessments scheduled at the same time may be 
initiated prior to the timepoint.  The order of assessments (as applicable to study visit) that should occur before dosing is: 1) PRO questionnaires, 2) vital signs, 
3) ECG, 4) PK sampling, 5) dose administration.  Blood sampling for safety laboratory assessments will be done prior to dosing.  The order of assessments (as 
applicable to the study visit) that should occur after dosing is: 1) vital signs, 2) ECG, 3) PK sampling.  All other procedures can be completed (as applicable to 
study visit) after the PK sample has been collected.  It is critical that the patients record the time of dose in their Patient Study Drug Administration Diary for the 
PK assessment and the site record the time of blood sampling. 
a. 
End of Treatment Visit (EOT) occurs 7 to 10 days after the last dose of study drug.  Assessments completed within 7 days prior to the last dose of study drug 
do not need to be repeated.  If a patient discontinues from the study early (Early Discontinuation [ED]), they will have an ED Visit within 7 to 10 days after 
the last dose of study drug. 
b. 
For patients who permanently discontinue study drug for any reason other than confirmed disease progression, tumor imaging and disease response 
assessments will continue to be performed every 12 weeks (± 7 days) for up to 12 months after the last dose of the study drug until disease progression, 
withdrawal of consent, initiation of new anticancer therapy, the patient is lost to follow-up or death, whichever comes first. 
• 
If a patient meets disease progression during the follow-up period according to RECIST v1.1 criteria, a tumor imaging and disease response assessment 
is not required. 
• 
If a patient permanently meets clinical disease progression during the follow-up period, a tumor imaging and disease response assessment does not need 
to be repeated if completed ≤ 28 days after the date of clinical disease progression. 
• 
Patients who have met disease progression will be contacted every 3 months for survival follow-up. 
c. 
An informed consent must be signed before any study procedures may be performed. 
d. 
Patients will receive a Patient Study Drug Administration Diary for each cycle.  Patients must record the date and time of each dose administration (Days 1 
to 14 [Cycle 1] and Days 1 to 7 [Cycle 2 onwards]), as well as any missed doses. 
e. 
All patients will be contacted by phone 1 day prior to every on-site visit for assessing signs and symptoms of coronavirus disease 2019 (COVID-19) and if 
they had any contact with a person who has tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  Patients will receive a 
follow-up phone call 30 days after last dose to follow-up on any ongoing AEs/SAEs. 
f. 
Medical history includes collection of data from any available historical genetic assays conducted to identify genetic variations.  For mCRPC patients 
only: Gleason score assessment will also be collected as part of the medical history of the patient. 
g. 
A complete physical examination, including weight, will be performed during the Screening Visit.  A symptom-directed physical examination will be 
performed prior to the first dose of study drug in Cycles 1 to 3, and every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.; or within 3 days before Day 1 
of the cycle) and at the EOT/ED Visit.  Abbreviated physical examinations may be conducted as needed and will focus on new symptoms and will include 
examination of relevant systems as identified by the Investigator.  Height will only be measured at Screening only.  Weight will be measured at Screening, 


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Cycles 2, 5 and every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.).  Physical examinations need to include the assessment of the perineal and anal 
region. 
h. 
Vital signs (oral or tympanic [both are accepted] temperature, pulse, respiratory rate and blood pressure) will be measured at Screening and during Cycle 1 at 
the following timepoints: predose and at 1 and 4 hours postdose on Days 1, 6 and 14.  Vital signs will be measured predose on Day 1 of Cycles 1 to 3, every 
second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
i. 
For all patients in Part 1 and the first 10 patients of each tumor type for Part 2 who will undergo PK sampling, a series of ECGs (in triplicate, within 1 to 
2 minutes apart) will be collected at Screening, and at the time points listed in Table 1-2 (Cycles 1 to 3).  For patients in Part 2 who will not undergo PK 
sampling, a series of ECGs (in triplicate, within 1 to 2 minutes apart) will be collected at Screening and a single ECG will be collected predose (within 30 
minutes prior to dosing to allow for sitting BP if needed) on Day 1 of Cycles 1 to 3.   
Electrocardiograms will be taken predose (within 30 minutes prior to dosing to allow for sitting blood pressure if needed) for all patients in both study parts 
on Day 1 of every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit.  Electrocardiograms will be obtained after 5 minutes of rest 
in the supine position. 
j. 
At each on-site visit, the study staff will question the patient about all concomitant medication used since their last on-site visit. 
k. 
For Cycle 1 Day 1 (C1D1) predose clinical laboratory evaluations (hematology, clinical chemistry, coagulation, urinalysis) may be performed within 3 days 
before the first dose of study drug and these results can be used in place of the C1D1 (predose) results.  Laboratory assessments for Cycle 1 Days 6 and 14 
should be performed on the respective days or within 1 day before dose administration on these days.  Clinical laboratory evaluations may be performed 
within 3 days before Day 1 of Cycles 2 and 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.), and at the EOT/ED Visit. 
l. 
Hematology: Complete blood count including hemoglobin, total white blood cell (WBC) count, differential WBC count and platelet count. 
m. 
Clinical chemistry: Sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, serum creatinine, bilirubin (total and direct), alkaline phosphatase, 
albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total cholesterol, uric acid, calcium, magnesium, phosphate, serum 
glucose. 
n. 
Coagulation parameters: Prothrombin time, international normalized ratio and activated partial thromboplastin time. 
o. 
Testosterone levels of ≤ 14.4 ng/dL must be maintained from baseline and throughout the study.  Testosterone levels will be measured at Screening, on Day 1 
of Cycles 1, 2 and 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
p. 
Serology: hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and human immunodeficiency virus.  Testing only applicable to patients 
who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis, or who are considered to be at risk for human 
immunodeficiency virus infection. 
q. 
Optional: SARS-CoV-2 testing to be done at Screening and additional time points.  Testing to be done if medically indicated and at the discretion of the 
Investigator.  SARS-CoV-2 testing is not required during the follow-up period.  Patients will be advised about the risks of COVID-19 infection and will be 
questioned by phone call prior to each on-site visit to assess their health and/or contact with persons who tested positive for COVID-19 infection. 
r. 
Postmenopausal women only. 
s. 
Only applicable to women of childbearing potential (WOCBP).  Serum pregnancy test to be performed at Screening and urine pregnancy test to be 
performed prior to Day 1 of Cycles 1 to 3, at every second cycle thereafter (i.e., Cycles 5, 7, 9 11 etc.) and at the EOT/ED Visit.  No pregnancy testing will 
be performed after this period.  WOCBP must continue using approved contraception methods for at least 3 months after discontinuation of the study drug.  
During the follow-up period, WOCBP will be questioned about their pregnancy status and use of contraception up to 3 months after last dose of study drug. 
t. 
At each on-site visit the study staff will question the patient about all adverse events (AEs) experienced since their last on-site visit.  Information on AEs and 
serious adverse events (SAEs) will be collected from signing of the informed consent form until 30 days after the last dose of study drug or until resolution 


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or stabilization of ongoing AEs deemed at least possibly related to the study drug, whichever is longer.  There will be a Safety Follow-up phone call to the 
patient conducted 30 days after the last dose of study drug for collection of AE/SAE information. 
u. 
Prostate-specific antigen (PSA; patients with metastatic castration-resistant prostate cancer [mCRPC] only) will have samples collected during Screening, on 
Day 1 of Cycles 1 to 5, every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at the 6-, 9- and 12-month Follow-up Visits for all 
patients including those who discontinue the study for any reason other than disease progression.  Patients who discontinue the study drug for reasons other 
than disease progression will continue to have PSA evaluated until disease progression, withdrawal of consent, initiation of new anticancer therapy, the end 
of the 12-month follow-up period or death, whichever comes first.  Patients who discontinue the study drug due to disease progression do not need to provide 
PSA samples during the Follow-up Visits. 
v. 
Tumor imaging and disease response assessments will be performed within 28 days prior to enrollment, every 8 weeks (± 7 days) from the first dose 
administration up to Week 26, and every 12 weeks (± 7 days) thereafter until disease progression, withdrawal of consent, initiation of new anticancer therapy, 
or death.  Patients who discontinue the study drug due to any reason other than disease progression will continue to have tumor imaging and disease response 
assessments performed every 12 weeks (± 7 days) for up to 12 months after the last dose of study drug until disease progression, withdrawal of consent, 
initiation of new anticancer therapy, the patient is lost to follow-up or death, whichever comes first.  Tumor imaging should ideally be performed during the 
rest period before the start of the next treatment cycle. 
• 
If a patient permanently discontinues the study drug due to disease progression according to RECIST v1.1 criteria, a tumor imaging and disease 
response assessment is not required. 
• 
If a patient permanently discontinues the study drug due to clinical disease progression, a tumor imaging and disease response assessment does not need 
to be repeated if completed ≤ 28 days of the last dose of study drug. 
Patients who permanently discontinue the study drug or the follow-up period due to withdrawal of consent, Investigator to obtain tumor imaging and conduct 
a disease assessment at the time of the ED Visit or final Follow-up Visit if the patient agrees.  A tumor imaging and disease response assessment does not 
need to be repeated if completed ≤ 28 days of the date of withdrawal of consent. 
At a minimum, imaging of the chest, abdomen and pelvis should be performed using consistent imaging modality (computerized tomography [CT] or 
magnetic resonance imaging [MRI]).  As far as possible, the same imaging method should be used for the patient throughout the study. 
w. 
Questionnaire to be completed at Screening, Day 1 of Cycle 3, Day 1 of Cycle 5 followed by every 4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.) and at 
the EOT/ED Visit.  Questionnaire to be completed prior to performing any other study visit assessments on the day of the visit. 
x. 
Questionnaire to be completed on Day 2 of Cycle 1, Day 1 of Cycle 3 and at the EOT/ED Visit.  Questionnaire to be completed prior to performing any other 
study visit assessments on the day of the visit (excluding predose clinical laboratory assessment for Cycle 1 Day 1 which may be completed within 3 days 
prior to Day 1). 
y. 
May be an in-person visit or a phone call.  Only applicable to patients who have met disease progression. 
z. 
Pharmacokinetic samples are to be obtained on Days 1, 2, 6, 14 and 15 of Cycle 1, and Days 1 and 8 of Cycles 2 and 3.  See PK sampling schedule in 
Table 1-3.  For Part 2, PK sampling will only be performed for the first 10 patients enrolled for each tumor group (mCRPC, breast cancer or non-small-cell 
lung cancer). 
aa. Pharmacodynamic blood samples to be collected at Screening or Cycle 1 on Days 1 and 15, prior to dosing on Day 1 of Cycle 3 (during the rest period after 
patients have completed 7-days of NOX66 treatment in Cycle 2, or predose on Day 1 of Cycle 3) and at the EOT/ED Visit.  See PD sampling schedule in 
Table 1-4. 
bb. Patients will be asked whether they are willing to provide both archival and fresh tissue biopsy samples OR only fresh tissue biopsy if they do not have 
archival tissue samples.  Available archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  Provision of a fresh 
biopsy sample and/or an archival tissue sample is optional.  See Table 1-5. 


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cc. On days when study drug and EBRT are to be administered, it is advisable that NOX66 is given at least 1 hour prior to EBRT.  Twice daily of NOX66 dosing 
should occur at least 10 hours apart.  Where 2 suppositories are administered per dosing, each suppository will be administered at least 5 minutes apart. 
dd. The recommended dose is up to 25 Gray (Gy) radiation therapy in 1 or 5 fractionated doses over 5 to 10 days (Days 2 to 11), depending on number of 
fractions to be administered, e.g., 8 Gy = 1 fraction over 1 day, 20/25 Gy = 5 fractions over 5 to 10 days.  EBRT must start on Day 2 of Cycle 1. 
 


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1.3.1 
Electrocardiogram Schedule 
Table 1-2 
Electrocardiogram Schedule: Part 1 (All Patients) and Part 2 (Only 
for First 10 Patients in Each Tumor Type) 
Sampling 
Time Point 
Cycle 1  
Day 1 
Cycle 1 
Day 2 
Cycle 1  
Day 6 
Cycle 1  
Day 14 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
Predose 
X† 
X 
X† 
X† 
X† 
X† 
1 hour (+ 15 minutes) 
X 
 
X 
X 
X 
X 
2 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
3 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
4 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
6 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
8 hours (+ 15 minutes) 
X a 
 
 
 
 
 
12 hours (+ 15 minutes) 
X a 
 
 
 
 
 
† Within 30 minutes prior to dosing to allow for sitting blood pressure if needed. 
a Only for Part 1. 
NOTE: For patients who will not undergo PK sampling in Part 2 of the study, a single ECG will be collected predose 
on Day 1 of each cycle up to Cycle 3. 
After Cycle 3 Day 1, ECGs will be taken predose (within 30 minutes prior to dosing to allow for sitting blood 
pressure if needed) for all patients in both study parts, on Day 1 of every second cycle thereafter (i.e., Cycles 5, 7, 9, 
11 etc.) and at the EOT/ED Visit. 
 
 


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1.3.2 
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1 
and Part 2 
Table 1-3 
Pharmacokinetic Sampling Schedule Following Morning Dose – 
Part 1 (All Patients) and Part 2 (Only for First 10 Patients in Each 
Tumor Type) 
Sampling 
Time Point 
Blood 
Volume 
(mL) 
Cycle 1 
Day 1 
Cycle 1 
Day 2* 
Cycle 1 
Day 6 
Cycle 1 
Day 14 
Cycle 1 
Day 15** 
Cycle 2 
Day 1 
Cycle 2 
Day 8*** 
Cycl
e 3  
Day 
1 b 
Cycle 3  
Day 8 b, 
*** 
Predose (within 
15 minutes prior to 
dosing) 
1 × 4 
X 
X 
X 
X 
X 
X 
Xc 
X 
Xc 
0.5 hour (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
1 hour (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
2 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
X 
 
X 
 
3 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
4 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
6 hours (± 10 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
8 hours (± 15 minutes)a 
1 × 4 
X 
 
 
 
 
 
 
 
 
12 hours (± 30 minutes; 
Prior to evening dose) a 
1 × 4 
X 
 
 
 
 
 
 
 
 
a.  Only for Part 1. 
b. Cycle 3 Days 1 and 8 samples only for patients in Part 2. 
c. Can be collected at home. 
* Sample to be collected approximately 12 hours post Day 1 evening dose. 
** Sample to be collected approximately 12 hours post Day 14 evening dose. 
*** Sample to be collected approximately 12 hours post Day 7 evening dose. 
 


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Table 1-4 
Pharmacodynamic Sampling Schedule – Part 1 and Part 2 (All 
Patients) 
Assay 
Blood Volume 
(mL) 
Screening/Cycle 1 
Day 1 Predose c 
Cycle 1 
Day 15 
Prior to 
Cycle 3 b 
End of Treatment/Early 
Discontinuation 
Chemokines, cytokines and 
lipids a 
1 × 4 
X 
X 
X 
X 
Circulatory tumor DNA a,d 
2 × 4 
X 
X 
X 
X 
a Plasma 
b Sample should be collected after the patient has completed 7 days of NOX66 treatment in Cycle 2 and prior to 
dosing on Day 1 of Cycle 3. 
c Baseline samples to be collected only after eligibility confirmation or on Day 1 prior to NOX66 administration. 
d Only at pre-selected sites that have peripheral blood mononuclear cell isolation capabilities in Australia and the 
United States of America. 
Table 1-5 
Optional Archival Tissue Collection and Fresh Biopsy Sampling 
Schedule – Part 1 and Part 2 (All Patients) 
Assay 
Screening 
After Cycle 3 
treatment 
Archival tissue if available (Optional) 
X 
 
Fresh biopsy (Optional) 
 
X 
NOTE: Available archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  
Provision of a fresh biopsy sample and/or an archival tissue sample is optional. 
 


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2 Introduction 
The term “study drug” throughout the protocol, refers to NOX66.  In addition, the terms 
participant and patient are used interchangeably. 
2.1 Study Rationale 
Idronoxil, which is the active ingredient of the NOX66 formulation, is a synthetic flavonoid 
derivative of genistein that inhibits external Ecto-NOX disulfide-thiol exchanger (ENOX) 2 to 
induce apoptosis2.  ENOX2 inhibition activates the sphingomyelinase pathway and deactivates 
the antiapoptotic protein kinase B (Akt) pathway, a key driver of radiotherapy resistance.  The 
targeted effect on ENOX2 has the potential to limit toxicity to non-cancer cells, which 
preferentially express ENOX1.  Previous studies have demonstrated improved radiation 
sensitivity in prostate cancer with flavonoid derivatives.  Early studies of intravenous and oral 
formulations of idronoxil were hampered by limited bioavailability.1  The Sponsor has sought to 
address the problem of extensive drug metabolism through the development of a rectal 
suppository dosage form.  With blood draining from the distal part of the rectum directly into the 
inferior vena cava, first pass liver metabolism can be avoided.  In the case of a diphenolic drug 
such as idronoxil, the bioavailability is augmented by the rectal mucosa being known to be 
devoid of transferase activity and therefore the phase II metabolism is significantly reduced.  
These two aspects combined are the basis for the rationale that idronoxil delivered via the rectum 
is subjected to less phase I and phase II metabolism than that observed for orally administered 
idronoxil.  NOX66 is a suppository dosage form of idronoxil in a proprietary fatty base 
containing a surfactant.  This formulation is novel in that a lipophilic active ingredient is 
dispersed in a lipophilic suppository base – compared with traditional suppository formulations 
whereby a hydrophilic base would normally be utilized.  Moreover, this suppository dosage form 
provides a slow and sustained release of idronoxil comparable to an intravenous infusion.2 
The first clinical study with NOX66 (NOX66-001A) was a Phase 1a/1b study in which NOX66 
was evaluated both as a monotherapy and in combination with carboplatin, in patients with 
refractory solid tumors.  Two breast cancer (BC) patients and one ovarian cancer patient enrolled 
in this study had reductions in target lesions size with one BC patient showing target lesion 
disappearance (as per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1.) at the end 
of the study. 
The NOX66-002A study evaluated NOX66 in combination with external beam radiotherapy 
(EBRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).  Twenty-five 
patients received radiation therapy and 7 to 16 days of NOX66 treatment in this study. 


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The overall radiological assessment according to RECIST v1.1 at 3 months for 19 evaluable 
patients resulted in 17 patients with disease control (1 patient in the 800 mg and 2 patients in 
1200 mg dose cohort with partial response [PR], 14 patients with stable disease [SD]) and 
2 patients, 1 each in the 400 mg and 800 mg cohorts, respectively, with disease progression.  At 
6 months and of the 15 evaluable patients, 1 continued to have PR and 60% continued to have 
SD.  There were two changes among the patients with PR in the 1200 mg cohort, with 1 patient 
not evaluable due to withdrawal and the other patient progressing to disease progression by 
RECIST v1.1 criteria while maintaining a prostate-specific antigen (PSA; 69%) and pain 
response (69% in overall pain score). 
The overall disease control rate (DCR) at 6 months was 66.6% (10/15), with 9 patients having 
SD and 1 patient PR.  The patient with PR also had a PSA decrease of 86% and a symptom 
control response of being 100% pain-free.  A clinical meaningful response in a non-irradiated 
lesion was also observed in the same patient, with a reduction in tumor size of 26.1% from 
baseline at 3 months and a continued decline to 49.3% at 6 months (abscopal response).  Four of 
15 patients had an abscopal response in non-irradiated lesions that were outside of the radiation 
field. 
NOX66 is designed to improve drug delivery and exposure of idronoxil to tumor cells.  This 
Phase 1b/Phase 2a clinical study will explore higher doses of NOX66 and expand the experience 
of NOX66 in men with mCRPC and patients with other solid tumors to determine the 
recommended Phase 2 dose (RP2D) and provide preliminary evidence on overall tumor response 
rate, survival, symptomatic relief of pain as well as other symptoms of this disease, and effects 
on PSA levels (for mCRPC patients only). 
2.2 Background 
Cancer is one of the greatest health challenges of our time with prostate cancer being the second 
most common cancer in men.  In 2018, over 1.2 million new cases of prostate cancer were 
diagnosed worldwide and there were 350 000 deaths due to the disease.3 
Traditional chemotherapy and radiotherapy are destructive treatments that, while inflicting 
damage on cancer cells, also damage other cells in the bodies of cancer patients.2  Genistein and 
its analogue daidzein are two isoflavone extracts of soy that cause a range of physiological 
effects, including regulation of the cell cycle and apoptosis and potent sensitization of cancer 
cells to radiotherapy and chemotherapy.  The active ingredient of NOX66, idronoxil, is an 
intermediate metabolite of daidzein with greater bioavailability and anticancer activity than 
genistein, making it a superior drug candidate.  Idronoxil has been demonstrated to have in vitro 
(half maximal inhibitory concentration [IC50] < 10 µM) and in vivo activity against a broad range 


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of cancer cell lines from breast, cervical, colorectal, gallbladder, head and neck, leukemia, 
melanoma, osteosarcoma, ovarian, prostate and renal origins.  By contrast, idronoxil is only 
mildly toxic to selected cell lines of non-cancerous origins.2 
The binding target of idronoxil is an enzyme present on the external membrane of cancer cells 
known as ENOX2.  This enzyme is responsible for maintaining the transmembrane electron 
potential (TMEP) of the plasma membrane.  Inhibition of ENOX2 results in the loss of TMEP, 
precipitating a build-up of protons in the plasma membrane and a catastrophic series of events in 
the sphingomyelin pathway leading to the blockage of sphingosine-1-phosphate (S1P) 
production.  ENOX2 is an oncogene whose expression is restricted to cancer cells.  As such, 
idronoxil binding is highly specific to tumor cells.2 
The primary biological effects of idronoxil stem from inhibition of the main pro-survival 
signaling checkpoints within the cancer cell, starting with S1P which is responsible for activation 
of the phosphoinositide 3-kinase (PI3) and Akt.  Depending on the degree of inhibition by 
idronoxil, the effect ranges from cell death (variously caspase-dependent and 
caspase-independent apoptosis) down to sub-lethal effects (including inhibition of resistance 
mechanisms).  Idronoxil has been shown in vitro to be highly selective for cancer cells and 
cytotoxic against multiple tumor cell lines.2 
While idronoxil displays monotherapy cytotoxicity, NOX66 is under clinical investigation as a 
sensitizer of chemotherapy and radiotherapy through its ability to block resistance mechanisms 
including deoxyribonucleic acid repair.  The degree of sensitization of chemotherapy agents, 
including carboplatin and doxorubicin, by idronoxil has been shown in vitro to be over 
2000-fold.2 
In clinical studies, orally and intravenously administered idronoxil has proven to be highly 
susceptible to phase II metabolism (believed to be > 99% in humans when dosed orally), 
resulting in extensive inactivation of the drug and limiting its clinical efficacy.  NOX66 is a 
formulation of idronoxil designed to avoid phase II metabolism thereby conserving its bioactivity 
and facilitating transport and delivery of the active form of idronoxil to tumor cells.  Rectal 
delivery reduces the possibility of phase II metabolism by bypassing first pass metabolism in the 
liver and avoiding the high level of phase II metabolic enzymes in the intestine.2 
A detailed description of the chemistry, pharmacology, efficacy and safety of NOX66 is 
provided in the Investigator’s Brochure (IB).2 


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2.3 Benefit/Risk Assessment 
Based on Phase 1 clinical studies (Study NOX66-001A [NCT02941523] and 
Study NOX66-002A [NCT03307629]) with NOX66 at dosages of 400 mg, 600 mg, 800 mg and 
1200 mg, treatment with NOX66 in combination with carboplatin (Study NOX66-001) in 
patients with solid tumors and low-dose EBRT in patients with prostate cancer 
(Study NOX66-002A) has been shown to be well tolerated with no emerging safety signals of 
concern. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of NOX66 can be found in the IB.2 
2.3.1 
Risk Assessment 
There was one treatment-emergent adverse event (TEAE), observed in Study NOX66-001A 
(patients with prostate cancer, BC, ovarian cancer, and lung cancer), of moderate (Grade 2) 
anemia possibly related to NOX66 when dosed at 800 mg as a monotherapy.  In combination 
with carboplatin the most common TEAEs of mild to severe anemia, neutropenia and 
hypocalcemia were attributed to carboplatin alone.  Of the four deaths occurring during the 
NOX66-carboplatin treatment, sudden death, in the absence of an autopsy, was conservatively 
attributed to possibly related to carboplatin and all other deaths were due to disease progression.2 
In combination with radiotherapy (Study NOX66-002A [patients with mCRPC]), AEs of mild 
dry mouth, stomatitis (oral mucositis) and fatigue, observed for patients receiving 400 mg, 
800 mg and 1200 mg NOX66, were possibly related to the treatment.2 
The majority of all other AEs were mild to moderate (Grades 1 to 2).  Excluding serious adverse 
events (SAEs), Grade 3 AEs were lymphopenia, nausea, vomiting, asthenia, elevated blood 
alkaline phosphatase, hypocalcemia, hypophosphatemia, back pain and bone pain, and spinal 
pain which were reported in 4 patients.  No Grade 4 AEs were reported.  None of these AEs were 
considered related to NOX66 by the Investigator. 
Pathmanandavel et al (2021) and Crumbaker (2020) conducted a Phase 1/2 trial of the 
combination of 177lutetium prostate-specific membrane antigen (PSMA) 617 (LuPSMA-617) in 
combination with NOX66 in men with end-stage mCRPC.  Previous trials of lutetium PSMA in 
men with mCRPC had demonstrated good safety and efficacy.  In this study, patients with 
mCRPC were administered NOX66 (400 mg to 1200 mg daily for 10 days) in combination with 
LuPSMA-617.  Results showed similar and consistent results when compared with the safety and 
tolerability profile from other studies.  The most frequent AEs were (Grade ≥ 2) anemia (n = 19), 


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fatigue (n = 9), xerostomia (n = 3), anal inflammation (n = 3), thrombocytopenia (n = 3), 
constipation (n = 1), and pneumonitis (n = 1).4 
To date the administration of NOX66 has not been associated with any increase in cardiac AEs 
and consequently has not shown any cardiac risk from initial clinical use.  There was one cardiac 
AE of pericarditis during NOX66 monotherapy which was of moderate severity and resolved.  
Cardiac monitoring and quantitative electrocardiogram (ECG) analysis before and after the 
period of dosing with NOX66 is included in the current study.2 
Patients with mCRPC participating in this study may also receive androgen deprivation therapy 
(ADT) during the study.  This standard of care (SOC) treatment has risks associated with 
receiving the treatment, however it is not foreseen that this SOC treatment will pose a higher risk 
to patients participating in this clinical study compared to other patients with mCRPC not taking 
part in this clinical study.  Patients with BC will be allowed background hormonal therapy during 
this study. 
During the study there is also the risk of spreading severe acute respiratory coronavirus 2 
(SARS-CoV-2) which is known to be transmissible via respiratory droplets.  The coronavirus 
disease 2019 (COVID-19) pandemic began in Wuhan, China, in December 2019 and became a 
global public health emergency in March 2020.  Given that the study enrolls patients with cancer 
who are in need of treatment, the protocol allows inclusion of patients with mCRPC for whom 
the Investigator determined that the risk of potential exposure to COVID-19 (e.g., as a result of 
travel to the site and considering any other co-morbidities or risk factors the patient may have) 
does not outweigh the potential benefit of receiving treatment.  Given that each site and/or 
country may be impacted differently during the COVID-19 pandemic and changes may occur at 
a rapid pace, each site should follow their own institutional guidelines, as well as making 
individual risk assessments of their sites ability to enroll and, when needed, to hold enrollment of 
patients. 
Measures to mitigate additional risks caused by the COVID-19 pandemic include: 
• 
The study is going to start enrolling only when the Sponsor and study site in collaboration 
deem it is safe to start the study.  In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic are 
lifted by the local authorities. 
• 
Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 


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• 
Patients will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat and fatigue throughout the study.  Once clinical signs 
of infection are reported by patients, the Investigator needs to determine whether samples can 
be collected, and safety data can be recorded on site.  If not, AEs and concomitant 
medications will be obtained via phone calls.  Daily body temperature measurements during 
outpatient visits will be implemented. 
• 
Confirmation of COVID-19 infection by laboratory assessment will be conducted based on 
availability (test capacity and turnaround time) of approved tests and on Investigator’s 
discretion.  This would include testing at Screening and may optionally be done at additional 
time points if the patient has been in contact with someone who tested positive or has any 
signs and/or symptoms of COVID-19 infection. 
• 
The probability of virus transmission will be controlled as much as possible by: 
o Advice for patients to adhere to local requirements for reduction of the public exposure 
while ambulatory. 
o All patients are contacted by phone 1 day prior to every visit for assessing COVID-19 
symptoms and signs and are asked not to attend the site in case of suspected COVID-19 
disease.  In addition, patients are asked for any contact with a person who has tested 
positive for SARS-CoV-2.  If applicable, patients will be referred to the local health care 
system for further follow-up and treatment. 
o Physical distancing and person-to-person contact restrictions will be applied during site 
visits. 
o Where physical distancing is not possible, personal protective equipment will be used by 
study patients (for example surgical face mask, and gloves) and staff (for example but not 
limited to masks, gloves, protectors, and medical suits) if deemed appropriate by the 
Investigators and site staff and guided by local requirements. 
• 
Patients will follow site policy in order to mitigate the additional risks caused by COVID-19.  
All medical measures, risk/benefit and restrictions associated with COVID-19 screening will 
be explained in the informed consent form (ICF). 
2.3.2 
Benefit Assessment 
Traditional cancer treatments (e.g., chemotherapy and radiotherapy) inflict damage on both 
cancer cells and healthy tissue cells as it is not target-specific.  In contrast, idronoxil has be 
shown in vitro to be highly selective for cancer cells and cytotoxic against multiple tumor cell 
lines as well as being only slightly toxic to non-cancerous cells. 


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A drawback observed in previous clinical studies with orally dosed NOX66 was its high 
susceptibility to phase II metabolism (believed to be > 99% in humans) which resulted in 
extensive inactivation of the drug and limited its clinical efficacy.  The Sponsor has sought to 
address this problem through the development of a suppository dosage form for rectal 
administration which avoids first pass liver metabolism and reduces phase II metabolism and can 
lead to greater bioavailability and clinical efficacy in patients.  Moreover, this dosage form 
provides a slow and sustained release of idronoxil compared to intravenously administered 
idronoxil. 
This study primarily aims to evaluate the safety and tolerability of NOX66 suppository dosage 
form and determining the RP2D in patients with mCRPC and other solid tumors (Part 1), and 
determining its effect on PSA response (in patients with mCRPC) and DCR (in patients with BC 
or non-small cell lung cancer [NSCLC]) (Part 2).  This study will further inform the dose 
regimen to be used in further clinical development of idronoxil as a potential target-specific 
treatment for various cancers including mCRPC and other solid tumors. 
2.3.3 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to patients participating in this study, the 
potential risks identified in association with NOX66 are justified by the anticipated benefits that 
may be afforded to patients with mCRPC and other solid tumors. 
3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives and Endpoints 
Part 1 (Dose Escalation): 
The primary objective for Part 1 will be determined 
based on the count of DLTs. 
To determine the MTD and RP2D of 
NOX66 in combination with 
low-dose EBRT in patients with any 
solid tumor 
• 
MTD is defined as the dose level at which no more 
than 1 patient out of 6 experiences a DLT at the 
end of Cycle 1. 
• 
RP2D is the highest dose administered at which no 
more than 1 patient out of 6 experiences a DLT at 
the end of Cycle 1 and the dosage form, including 
the dosing frequency, is acceptable to patients. 


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Objectives 
Endpoints 
Part 2 (Dose Expansion): 
 
Arm 1: To evaluate the effect of 
NOX66 on PSA response in patients 
with mCRPC. 
 
Arm 2: To evaluate the effect of 
NOX66 on DCR in patients with BC 
and NSCLC. 
• 
PSA response is defined as the proportion of 
patients with a reduction in PSA in plasma (ng/mL) 
of ≥ 30% from baseline at the end of Cycles 3 and 
6. 
• 
DCR is measured by the percentage of patients 
with a best overall confirmed response of CR or 
PR and SD. 
Secondary Objectives and Endpoints 
Characterize the safety and 
tolerability of NOX66 
Safety and tolerability of NOX66 as determined by 
AEs, TEAEs, clinical laboratory evaluations, vital 
signs, 12-lead ECG and physical examinations. 
Evaluate the safety and tolerability of 
both doses of EBRT 
Safety and tolerability of both doses of EBRT as 
determined by AEs, TEAEs, clinical laboratory 
evaluations, vital signs, 12-lead ECG and physical 
examinations. 
Evaluate the exposure of idronoxil 
Concentration of idronoxil and selected metabolites in 
plasma and derived PK parameters, including but not 
limited to: Cmax, Tmax, AUC(0-t), AUC(0-6), AUC(0-12), 
AUC(0-inf), Cmin and t½, as data permit. 
Evaluate the preliminary clinical 
efficacy of NOX66 plus low-dose 
EBRT in patients with mCRPC and 
other solid tumors 
Preliminary clinical efficacy as determined by: 
• 
Change from baseline in PSA (mCRPC only) at 
any time point. 
• 
Overall response rate assessed by RECIST v1.1 
criteria (all tumor types) and PCWG-3 criteria 
(mCRPC). 
• 
Duration of response (for patients with measurable 
disease). 
• 
Change from baseline ECOG scores. 
• 
Change from baseline in tumor size and number. 
• 
PFS and OS. 
Explore the effects of NOX66 on 
pain and other cancer-related signs 
and symptoms 
Effects on pain and other cancer-related signs and 
symptoms as determined by: 
• 
Change from baseline in pain scores based on the 
BPI-SF questionnaire. 
• 
SREs and SSEs. 
• 
Change of dose and frequency of morphine 
administration and analgesic use. 


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Objectives 
Endpoints 
Evaluate the QoL using PRO 
questionnaires 
QoL as assessed by: 
• 
Change from baseline in PEQ. 
• 
Change from baseline in EORTC-QLQ-C30. 
• 
Change from baseline in FACT-P (mCRPC only). 
Exploratory Objectives and Endpoints 
Characterize the relationship 
between pharmacodynamic 
biomarkers and idronoxil plasma 
concentrations (if a meaningful 
change is observed) 
• Change in biomarkers (cytokines, chemokines and 
ctDNA) from baseline. 
• Change in lipid profile from baseline. 
AE = adverse event; BC = breast cancer; BPI-SF = Brief Pain Inventory – Short Form; CR = complete response; 
ctDNA = circulatory tumor deoxyribonucleic acid; DCR = disease control rate; DLT = dose-limiting toxicity; 
EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
for Cancer Patients; FACT-P = Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic 
castration-resistant prostate cancer; MTD = maximum tolerated dose; NSCLC = non-small-cell lung cancer; 
OS =  overall survival; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; PRO = Patient Reported 
Outcome; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid 
Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; SRE = skeletal-related events; 
SSE = symptomatic skeletal events; TEAE = treatment-emergent adverse event 
 
4 Study Design 
4.1 Overall Design 
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, 
RP2D, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil 
when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) 
and patients with mCRPC, BC and NSCLC (Part 2) who are eligible for low-dose EBRT for at 
least one symptomatic or minimally symptomatic lesion (for the prevention of symptoms).  The 
study will be performed in approximately 14 sites in Australia, United States (US) and Europe.  
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion).  The study 
design allows an exploration of different doses of NOX66 (800 mg, 1200 mg, 1600 mg and 
2400 mg) with safety monitoring to ensure the safety of the patients.  A Safety Steering 
Committee (SSC) will review available safety data after the first cycle (21 days) of each dose 
cohort of NOX66 in Part 1 to determine the maximum tolerated dose (MTD)/RP2D. 
In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day 
cycle.  From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest 
period on a 14-day cycle.  Patients will continue to receive NOX66 on a cyclical basis until 


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disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer 
therapy, withdrawal of the patient by the Investigator or termination of the study by the Sponsor. 
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gray (Gy) as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be administered on Day 2 of Cycle 1 and the remaining dose 
fractions will be given between Day 3 and Day 11.  The choice of one of the EBRT 
dose/fractions stated above will be at the discretion of the Investigator and will be determined by 
the clinical requirements of the patient.  EBRT will be administered according to the institutional 
protocol. 
Additional EBRT at the dose levels/fractions stated above may be given during the study.  
However, should additional EBRT be considered necessary during the study (Cycle 2 onwards), 
the Investigator should communicate this to the Medical Monitor for team acknowledgment 
since extra doses could impact study results. 
The expected study duration for each patient from initial administration of NOX66 until the last 
study visit is determined by the number of treatment cycles each patient receives plus the 
follow-up period, which is from the last dose of NOX66 on study until death or the patient is lost 
to follow-up. 
The study will finish when the last patient enrolled in Part 2 completes 6 months of treatment 
and all patients receiving study drug at that time will be switched to the NOX66 compassionate 
access program.  Those patients on the compassionate access program will continue to receive 
NOX66 treatment until disease progression or unacceptable toxicity.  The patients will be 
followed until death, or the patient is lost to follow-up. 
There will be a Screening period of up to 27 days (Days -28 to -2).  Each patient will attend the 
study center on Day -1 of Cycle 1 for eligibility assessments and on all PK days 
(Cycle 1: Days 1, 2, 6, 14 and 15; Cycles 2 and 3: Days 1 and 8).  Patients in Part 1 may require 
an overnight stay on Day 1 of Cycle 1.  On Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3, the NOX66 morning administration will occur at the study center under medical 
supervision.  During these days blood samples for PK analysis will be collected as per the 


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schedule mentioned in Table 1-3.  In addition to PK samples, patients will be monitored for 
cardiac effects using 12-lead ECGs (Table 1-2).  NOX66 will be self-administered by the 
patients or administered by their care giver at home on all other dosing days as well as the 
evening doses of NOX66 on PK days (Cycle 1: Days 2, 6 and 14; Cycles 2 and 3: Day 1).  The 
evening dose of Day 1 of Cycle 1 (in Part 1 only) will be administered at the clinical unit.  
Patients or care givers should always wear gloves when handling and/or during administration of 
NOX66.  The use of a small amount of water-soluble lubricant is advised before rectal 
administration.  No oil- or wax-based lubricants should be used during rectal administration.  
Further administration instructions are provided in the “Instructions for Administration of 
NOX66 Suppositories” document.  Patients will also attend the study center for EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively) on Days 2 to 11 of Cycle 1 depending 
on the number of fractions to be administered.  From Cycle 2 onwards only NOX66 will be 
administered for 7 days followed by a 7-day rest period (as indicated above).  Patients with 
mCRPC may also receive ADT as maintenance therapy and patients with BC may receive 
background hormonal therapy during this study.  No other anticancer therapy will be allowed 
during the study.  Patients will have an End of Treatment (EOT) Visit within 7 to 10 days after 
the last dose of study drug.  If a patient discontinues the study early (Early Discontinuation 
[ED]), the patient will have an ED Visit within 7 to 10 days after the last dose of study drug. 
Patients in both study parts will be followed up by phone for AEs/SAEs for 30 days after the last 
dose of study drug or until resolution or stabilization of ongoing AEs/SAEs deemed at least 
possibly related to the study drug, whichever is longer.  All patients (including patients who 
discontinued the study early for reasons other than disease progression) will be followed up 
approximately every 12 weeks (± 2 weeks) after completion of the treatment period for disease 
progression up to 12 months, and for safety until death, or the patient is lost to follow-up.  
Patients who discontinued the study early for reasons other than disease progression will attend 
the clinical unit for the follow-up visits.  Patients will receive the study drug until disease 
progression, unacceptable toxicity, withdrawal of consent, initiation of new anticancer therapy, 
withdrawal of the patient by the Investigator or termination of the study by the Sponsor.  Tumor 
imaging and disease response assessments will be performed for up to 12 months after the last 
dose of study drug until disease progression, withdrawal of consent, initiation of new anticancer 
therapy, the patient is lost to follow-up or death, whichever comes first. 


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The study will include 4 dose cohorts (Part 1) and 2 treatment arms (Part 2): 
• 
Part 1: Eligible patients with any solid tumor will be enrolled in one of 4 dose cohorts: 
o Dose Cohort 1: 800 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on the number of fractions to be administered).  From Cycle 2 
onwards, 800 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 2: 1200 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1200 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 3: 1600 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1600 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 4: 2400 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
2400 mg NOX66 will be administered on Days 1 to 7. 
• 
Part 2: Eligible patients will be enrolled in 1 of 2 treatment arms: 
o Arm 1 – patients with mCRPC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 
to 11 of Cycle 1, depending on number of fractions to be administered).  From Cycle 2 
onwards, RP2D NOX66 will be administered on Days 1 to 7. 
o Arm 2 – patients with BC and NSCLC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT 
(Days 2 to 11 of Cycle 1, depending on number of fractions to be administered).  From 
Cycle 2 onwards, RP2D NOX66 will be administered on Days 1 to 7. 
Patients will have a rest period (no NOX66 administration) on Days 15 to 21 of Cycle 1 and 
Days 8 to 14 of Cycle 2 onwards (Parts 1 and 2). 
The study schemes are provided in Figure 1–1 (Part 1) and Figure 1–2 (Part 2), and the Schedule 
of Activities (SoA) is provided in Table 1-1 (Parts 1 and 2). 
4.1.1 
Part 1 (Dose Escalation) 
Approximately 30 patients with any solid tumor who require low-dose EBRT will be enrolled 
sequentially to the four planned NOX66 dose groups (Dose Cohort 1: 800 mg [3 to 6 patients]; 
Dose Cohort 2: 1200 mg; Dose Cohort 3: 1600 mg; Dose Cohort 4: 2400 mg [3 to 8 patients in 
each of Dose Cohorts 2 to 4]; total daily dose administered twice a day [BID]).  At least 
2 patients enrolled in Dose Cohorts 2 to 4 must have mCRPC. 


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The proposed dose regimen for Part 1 is given in Table 4-1.  No intra-subject dose escalation is 
allowed. 
Table 4-1 
Proposed Doses for NOX66 (Part 1) 
 
Dose Cohort 
1 
2 
3 
4 
Total daily dose 
800 mg 
1200 mg 
1600 mg 
2400 mg 
Dosing regimen 
400 mg BID 
600 mg BID 
800 mg BID 
1200 mg BID 
Number of suppositories per 
day 
2 × 400 mg 
2 × 600 mg 
4 × 400 mg 
4 × 600 mg 
BID = twice daily 
All patients will be closely monitored for any dose-limiting toxicities (DLTs) up to Day 21 of 
Cycle 1. 
Dose escalation will be based on an adapted “3+3” design, where dose cohorts will be expanded 
for up to 6 patients (Dose Cohort 1) in the event of DLT or up to 8 patients (Dose Cohorts 2 to 4) 
to allow for robust estimation of PK parameters after being deemed “safe” based on the 
traditional “3+3” design. 
At each dose level, 3 patients will initially be treated with NOX66. 
• 
If none of the first 3 patients enrolled in Cohort 1 experience a DLT during the first treatment 
cycle, the dose will be escalated to the next level. 
• 
If none of the first 3 patients experience a DLT during the first treatment cycle of Cohorts 2 
to 4, then the dose level will be deemed “safe” and up to 5 additional patients will be enrolled 
to the current dose level for estimation of PK parameters.  At the same time (with the 
exception of Cohort 4), the next dose level will be initiated and the first 3 patients will be 
enrolled to the escalated dose. 
• 
If 1/3 patients experience a DLT, an additional 3 patients will be enrolled.  If 1/6 patients 
experience a DLT then this dose level will be deemed “safe” and, for Cohorts 2 to 4, 2 more 
patients may be enrolled for estimation of PK parameters.  At the same time, the next dose 
level will be initiated and the first 3 patients will be enrolled to the escalated dose. 
• 
If > 1/3 or > 1/6 patients experience a DLT, then dose escalation will be halted, and the 
previous dose will be declared as the MTD. 
If the 1200 mg dose is not tolerable (i.e., 2 or more patients with DLTs), an additional 3 patients 
will be enrolled in the 800 mg dose cohort in order to declare 800 mg as the MTD (if no more 
than 1/6 patients experience a DLT). 


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If no DLT is observed at 2400 mg (Dose Cohort 4), dose escalation will be stopped.  The 
proposed highest dose level (2400 mg) will be declared the RP2D. 
There will be a temporary halt for enrollment after the first 3 patients are enrolled in each cohort 
until the SSC clears that the dose level is safe to continue the dose escalation.  During the SSC 
meeting for NOX66 dose escalation decision, the safety and tolerability of both EBRT doses 
(8 Gy and 20/25 Gy) will also be evaluated.  For details on DLT evaluation, see Section 7.1.2.2. 
DLT monitoring will be applicable for all patients enrolled in each cohort, including patients 
enrolled for the purpose of PK analysis; as well as the decision rule for the additional PK patients 
(i.e., stopping dose escalation). 
4.1.2 
Part 2 (Dose Expansion) 
Part 2 will be expanded to enroll additional patients with mCRPC (Arm 1), BC and NSCLC 
(Arm 2).  All patients will be treated with NOX66 RP2D along with low-dose EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively). 
Part 2 will enroll 2 treatment arms: 
• 
Arm 1 (n = 40): Patients with mCRPC. 
• 
Arm 2 (n = 24 to 30): Patients with BC and NSCLC. 
4.2 Scientific Rationale for Study Design 
Better SOC treatments for patients with prostate cancer and patients with other solid tumors, who 
have exhausted treatments, are needed.  Based on the positive results observed in Phase 1 clinical 
studies with NOX66, further investigation is warranted. 
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion).  During 
Part 1, four dose levels of NOX66 will be examined to determine the MTD and RP2D to be used 
in further clinical development of NOX66.  In Part 2, the confirmed RP2D dose level will be 
further examined in patients with mCRPC, BC and NSCLC.  Part 2 will also examine the effect 
of NOX66 on PSA of patients with mCRPC and the tumor response in patients with BC and 
NSCLC. 
Radiotherapy (i.e., low-dose EBRT) will be provided to patients during this study.  Low-dose 
EBRT is administered for the treatment of symptomatic lesions and/or to prevent asymptomatic 
lesions from becoming symptomatic.  Low-dose EBRT (8 Gy or 20/25 Gy as 1 or 5 fractionated 
doses, respectively) will be administered in this study for symptom control of lesions and 


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prevention of signs and symptoms.  The safety of the combination of NOX66 and EBRT has 
been tested in men with symptomatic mCRPC1 (see IB2 for details). 
The starting dose, dose escalation decision points and patient population size are based on 
accepted methodology for Phase 1/Phase 2 studies. 
In the previous study (NOX66-002A), the doses of 400 mg, 600 mg, 800 mg and 1200 mg of 
NOX66 were explored in combination with low-dose EBRT in patients with mCRPC.  The 
highest dose tested in this study was 1200 mg and a total of 15 patients have been treated with 
this dose.  There were no DLTs reported in that study.  Based on the NOX66-002A study safety 
and efficacy data this planned study is designed to continue the dose escalation from 
800 mg (400 mg BID) to 1200 mg (600 mg BID) to 1600 mg (800 mg BID) followed by 
2400 mg (1200 mg BID), if tolerable. 
In the previous trial, the total duration of NOX66 treatment was up to 16 days and low-dose 
EBRT of 20 Gy was given in 5 fractionated doses over 5 to 7 days.  NOX66 will be administered 
in this planned study on a 21-day cycle basis (14 days on treatment followed by 7 days off 
treatment) during Cycle 1, and on a 14-day cycle basis (7 days on treatment followed by 7 days 
off treatment) from Cycle 2 onwards.  NOX66 will be administered until disease progression, 
unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the 
patient by the Investigator or termination of the study by the Sponsor. 
The timings of safety and PK assessments in the study have been designed on the basis of 
non-clinical and clinical findings.  These data will be important to evaluate exposure-response 
relationships for efficacy and safety in mCRPC and other tumor types. 
As part of the clinical drug development program for NOX66, the Sponsor plans to include 
investigations into PD biomarker profiles and their relation to study drug effect at the intended 
dosage.  These biomarkers will be derived from blood samples taken during the study.  There are 
many potential benefits to this biomarker research, including the possibility to identify patients 
most likely to benefit from treatment, explain outliers and non-responders or explain adverse 
reactions related to study drug exposure.  This research may result in an understanding of the 
impact of variation between individuals and how it can be utilized to bring better drug products 
to the clinic. 


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4.3 Justification for Dose 
The selected starting dose, 800 mg NOX66 (total dose; 400 mg BID), has been used in a 
previous clinical trial (NOX66-002A) and was shown to be safe and well tolerated.  This dose 
level is the possible lowest BID dose of NOX66. 
Low-dose EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively) is 
considered SOC in this patient population.  The choice of dose/fraction is at Investigator’s 
discretion based on patient’s need.  Site will need to follow institutional practice for low-dose 
EBRT administration. 
4.4 End of Study Definition 
Once a patient completes or discontinues study drug, he/she will be followed up every 12 weeks 
(± 2 weeks) after the last dose of study drug for disease progression up to 12 months, and for 
safety until death or the patient is lost to follow-up. 
For the entire study, study completion is defined as the last visit of the last patient for any 
protocol related activity (last patient, last visit), including telephone contact.  For individual 
patients, study completion is defined as the time of the patient’s last data collection. 
The study will finish when the last patient enrolled in Part 2 completed 6 months of treatment; all 
patients receiving study drug at that time will be switched to the NOX66 compassionate access 
program.  Those patients on the compassionate access program will continue to receive NOX66 
treatment until disease progression or unacceptable toxicity.  These patients will be followed 
until death, or the patient is lost to follow-up. 
5 Study Population 
The study population will consist of patients with mCRPC, BC, NSCLC or other solid tumors 
who have failed at least one line of prior treatment and for whom, according to the Investigator, 
are eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion 
(for the prevention of symptoms). 


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5.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent 
1. Patient is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
Type of Patient and Disease Characteristics 
2. Patient has a minimum life expectancy of 6 months. 
3. Patient is 18 years or older at the time of signing the informed consent. 
4. Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid 
tumors. 
5. Confirmed metastatic disease by imaging (e.g., bone scans, X-rays, ultrasound, computerized 
tomography [CT], magnetic resonance imaging [MRI]). 
6. Documented disease progression (e.g., based on radiographic imaging, PSA or other clinical 
parameters) following first or later lines of anticancer systemic treatment. 
7. Patient is eligible for low-dose EBRT for at least one lesion. 
8. Patients with prior RT are eligible, only if there is no potential for field overlap between the 
prior RT and the planned RT. 
9. For patients with BC or NSCLC: Patient must have at least one measurable lesion as per 
RECIST v1.1 (in Part 2 only). 
10. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
11. Adequate bone marrow function defined as: 
• 
Absolute neutrophil count ≥ 1.5 × 109/L. 
• 
Platelet count ≥ 100 × 109/L. 
• 
Hemoglobin ≥ 9.0 g/dL (with or without transfusion). 
12. Adequate renal function defined as: 
• 
Creatinine clearance as measured by the Cockcroft-Gault equation > 30 mL/min. 


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13. Adequate liver function defined as: 
• 
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN; patients with confirmed 
Gilbert’s syndrome may be included in the study). 
• 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (or 
≤ 5 × ULN in patients with liver metastasis).  Elevated alkaline phosphatase is not 
exclusionary if due to the presence of bone metastasis and liver function is otherwise 
considered adequate in the Investigator’s judgement. 
Metastatic Castration-resistant Prostate Cancer 
14. Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained 
throughout the duration of the study. 
15. Patient has evidence of symptomatic and/or progressive disease.  Progressive disease is 
defined as any one of the following: 
• 
Radiographic disease progression in soft tissue (nodule or visceral metastasis) and/or 
bone with or without PSA progression.  Objective evidence of increase in radiographic 
lesions or the appearance of 2 or more new lesions. 
• 
Prostate-specific antigen progression: At least 3 consecutive rising PSA levels (≥ 2 to 
5 ng/mL) separated by at least 1 week, with castrate levels of testosterone. 
Breast Cancer Patients 
16. Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen 
receptors alone).  Breast cancer patients are allowed to be on background hormonal 
treatment. 
Contraception 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
NOTE: The reliability of sexual abstinence for male or female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 


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Male Patients: 
17. Patient must have had a vasectomy or must agree to use a highly effective contraception as 
detailed in Section 10.4 of this protocol during the treatment period and for at least 3 months 
after the last dose of study drug and refrain from donating sperm during this period. 
Female Patients: 
18. A female patient is eligible to participate if she is not pregnant (see Section 10.4), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4. 
OR 
• 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 and not to 
donate ova during the treatment period and for at least 3 months after the last dose of 
study drug. 
5.2 Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Patient has tumor involvement of the central nervous system. 
2. Impaired cardiac functioning or clinically significant cardiac disease, including the 
following: 
• 
Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study 
drug. 
• 
Corrected QT interval (QTc) using Fridericia’s formula (QTcF) > 470 msec on screening 
ECG (average of triplicate measurement will be used). 
• 
Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
NOTE: Patients with a history of coronary artery disease, revascularization and/or stable 
coronary artery disease are not excluded. 
3. Uncontrolled hypertension despite two concomitant antihypertensive therapies, defined as 
supine systolic blood pressure ≥ 150 mmHg or diastolic blood pressure > 100 mmHg based 
on a mean of three measurements at approximately 2-minute intervals. 


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4. Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis. 
5. Patients for whom administration of the suppositories are likely to cause pain or difficulties 
in absorption (e.g., inflamed hemorrhoids, fissures or lesions of the anus or rectum). 
6. Patients with fecal impaction or uncontrolled irritable bowel disease. 
7. Patients with inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) will be 
excluded, even if the condition is well controlled. 
8. Active or chronic infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C.  Screening of patients with serology testing for these viruses is not required.  
However, patients who have a past history of viral hepatitis or in whom there is a current 
suspicion of viral hepatitis will have serology testing for hepatitis B and hepatitis C 
performed to determine whether there is any current evidence of ongoing infection with these 
viruses.  Patients considered to be at risk for HIV infection should have HIV testing 
performed.  If the test result is negative, the patient will be allowed to participate in the study. 
NOTE: Patients with chronic HIV infection, on ongoing treatment with anti-viral 
medications, who have an undetectable viral load are not considered to be infectious and can 
be included in this study. 
9. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory 
finding that, in the Investigator’s opinion, gives reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, render the patient at high risk from treatment complications or interferes with 
obtaining informed consent. 
10. Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard 
therapy will be excluded. 
11. Major surgery within 4 weeks or minor surgery or biopsy within 1 week of the first dose 
administration. 
12. Patients who have had RT to the region of the rectum or will require RT to the region of the 
rectum during the trial. 
NOTE: Metastatic castration-resistant prostate cancer [mCRPC] patients who have received 
prior prostate or prostate fossa radiation and radiation to nearby lymph nodes, where the 
rectum is not the target, can be included in this study. 


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Prior/Concomitant Therapy 
13. Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal 
medications within 14 days before the first dose administration.  Infections (e.g., urinary tract 
infection) controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per 
institutional guidelines are acceptable. 
14. Receiving or having received anticancer treatment within the following period prior to the 
first dose administration: 
• 
Cytotoxic treatment: 3 weeks. 
• 
Non-cytotoxic drugs, including small molecule investigational products: 3 weeks or 
5 terminal half-lives from plasma (whichever is the longest). 
• 
Biological products including investigational immune-oncology agents: 4 weeks. 
• 
Radiation with a limited field for palliation: 4 weeks. 
• 
Radiation to > 30% of the bone marrow: 4 weeks. 
• 
Lung radiation: 60 days. 
15. Patient has received corticosteroids at a dose of > 10 mg prednisone/day or equivalent for 
any reason within 4 weeks prior to receiving the first dose administration. 
16. History of hypersensitivity to active or inactive excipients of study drug or drugs with a 
similar chemical structure or class to the study drug. 
Other Exclusions 
17. Patient is not willing to use suppositories. 
18. Judgement by the Investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 
19. Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for 
SARS-CoV-2 prior to Screening or enrollment, or has clinical signs and symptoms consistent 
with SARS-CoV-2 infection; e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive 
SARS-CoV-2 test result within 2 weeks prior to Screening.  Patients who had symptomatic 
COVID-19 disease less than 1 month prior to Screening will be excluded.  If a patient has 
had a severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically 
ventilated) within 4 weeks of Screening, or have any sequelae of infection or ongoing 
infection, the patient will also be excluded.  If the patient has had recent (within previous 
14 days) exposure to someone who has COVID-19 symptoms, been in contact with someone 


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who has tested positive for COVID-19 or visited a COVID-19 treatment facility, the patient 
may be re-evaluated for participation in the study after undergoing an isolation period of at 
least 10 days and having a negative SARS-CoV-2 RT-PCR test prior to enrollment. 
5.3 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled in the study.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities.  
Minimal information includes demography, reason for screen failure (e.g., eligibility 
requirements failed), and any SAEs will be recorded in the electronic case report form (eCRF). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  This will be assessed on a case-by-case basis and requires Sponsor and Clinical 
Research organization (CRO)’s prior approval before the patient is rescreened.  Rescreened 
patients should be assigned a different unique participant number from the initial screening.  The 
previous screening number will be noted separately for reference purposes. 
5.3.1 
Screening and Enrollment Log and Participant Identification Numbers 
The patient’s enrollment will be recorded in the Screening and Enrollment Log. 
Upon screening, each patient will receive a unique participant identification number.  Participant 
numbers must not be re-used for different patients. 
6 Study Drug 
Study drug is defined as any investigational drug(s) (including marketed product[s]) intended to 
be administered to a study participant according to the study protocol. 
On days when study drug and EBRT are to be administered, it is advised that NOX66 is given at 
least 1 hour prior to EBRT. 
6.1 Study Drug(s) Administered 
Details on study drug administered during this study are given in Table 6-1. 
Table 6-1 
Study Drug(s) Administered 
 
Part 1 
Part 2 
Dose Cohort/ 
Arm: 
Dose  
Cohort 1 
Dose 
Cohort 2 
Dose  
Cohort 3 
Dose  
Cohort 4 
Arm 1 
Arm 2 


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Drug Name: 
NOX66 
800 mg 
NOX66 
1200 mg 
NOX66 
1600 mg 
NOX66 
2400 mg 
RP2D 
RP2D 
Type: 
Small molecule 
Dosage 
Formulation: 
Suppository containing idronoxil in a lipophilic base 
Unit Dose 
Strength(s): 
400 mg or 600 mg 
Dosage Level(s): 
1 x 400 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
800 mg. 
1 x 600 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
1200 mg. 
2 x 400 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
1600 mg. 
2 x 600 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
2400 mg. 
To be 
determined 
To be 
determined 
Route of 
Administration: 
Rectal 
Use: 
Interventional 
IMP and NIMP: 
IMP 
Sourcing: 
Provided centrally by the Sponsor. 
Dosing 
Instructions: 
Twice daily NOX66 dosing should occur at least 10 hours apart.  Where 2 suppositories are 
administered per dosing, each suppository will be administered at least 5 minutes apart.  The 
same administration schedule should be adhered to on the days when EBRT is administered.  
Patients or care givers should always wear gloves when handling and/or during 
administration of NOX66.  The use of a small amount of water-soluble lubricant is advised 
before rectal administration.  No oil- or wax-based lubricants should be used during rectal 
administration.  Patients will be provided with an “Instructions for Administration of 
NOX66 Suppositories” that contains further details. 
Packaging and 
Labeling: 
Each suppository is supplied in individually sealed PVC suppository packaging shells and 
boxed in appropriate quantities for the clinical study.  Each box will be labeled as required 
per country requirement. 
IMP = investigational medicinal product; RP2D = recommended Phase 2 dose 
 
From Cycle 3 onwards, study drug for 2 cycles will be dispensed every second cycle 
(i.e., Cycles 5, 7, 9, 11 etc.).  From Cycle 5 onwards, on-site visits will occur on a 28-day 
(4 weekly) basis, i.e., patients will visit the clinical unit every second cycle.  After Cycle 5, the 
next patient visit will therefore be Cycle 7, followed by Cycle 9, etc. until the patient completes 
the treatment period or is withdrawn. 
In patients who have regular bowel movements (i.e., within several hours after waking), patients 
will be instructed to insert the suppository after the bowel movement.  To promote regular bowel 
movements, patients should be encouraged to consume a high fiber diet, with adequate amounts 
of water.  In those patients who are not on a regular bowel movement schedule, insertion of the 


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suppository should occur at regularly scheduled times individualized for the patient (but 
approximately 10 hours apart). 
For Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 and 3 (PK days), once the suppository 
is inserted in the rectum and defecation occurs within 2 hours after the administration, the 
remaining doses should be administered at the prescribed time as scheduled.  No re-dosing is 
permitted if defecation occurs within 2 hours of administration. 
The dosing time for suppository/ies administration must be recorded by the patient in the Patient 
Study Drug Administration Diary which must be brought to the study center at each on-site visit. 
6.1.1 
Radiotherapy 
The choice of dose/fraction as stated below is Investigator’s discretion based on patient’s need.  
Sites will need to follow institutional practice and the guidance provided in Appendix 10 
(Section 10.10) for low-dose EBRT administration. 
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gy as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be on Day 2 of Cycle 1 and the remaining dose fractions will 
be given between Day 3 and Day 11.  The choice of one of the EBRT dose/fractions as stated 
above will be at the discretion of the Investigator and will be determined by the clinical 
requirements of the patient.  A maximum of 2 sites can be irradiated concurrently in conjunction 
with NOX66 during Cycle 1.  EBRT will be administered according to the institutional protocol. 
Additional EBRT at the dose levels/fractions stated above may be given during the study.  
However, should additional EBRT be considered necessary during the study (Cycle 2 onwards), 
the Investigator should communicate this to the Medical Monitor for team acknowledgment 
since extra doses could impact study results. 
6.2 Preparation, Handling, Storage, and Accountability 
The Investigator or designee must maintain a log to confirm appropriate temperature conditions 
(2°C to 8°C [35.6°F to 46.4°F], away from direct light) have been maintained during transit for 


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all study drug received and any discrepancies are reported and resolved before use of the study 
drug. 
Patients must be advised that during travel from the study center to their homes the study drug 
must be stored at 2°C to 8°C (35.6°F to 46.4°F), away from direct light, and they should avoid 
leaving the study drug in their vehicle on a hot day.  They should also not keep the study drug on 
their person as the study drug will melt at body temperature.  At home the study drug should be 
stored in the fridge and handled as little as possible upon administration to prevent melting.  
Further details are provided in the “Instructions for Administration of NOX66 Suppositories”. 
Only patients enrolled in the study will receive study drug and only authorized site staff will 
supply or administer study drug.  All study drugs must be stored in a secure, environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator or designated staff (where applicable) is responsible for study drug 
accountability, reconciliation and record maintenance (e.g., receipt, reconciliation and final 
disposition records). 
Further guidance and information are provided in the “Instructions for Administration of NOX66 
Suppositories” document that will be provided by the Sponsor to patients and study staff. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study.  Each site must submit a completed Participant Enrollment Form to 
the Sponsor or CRO designee for approval to patient in the study.  The Sponsor’s representative 
(Parexel) will review the information to verify that the patient meets all inclusion criteria and 
none of the exclusion criteria to determine if the patient is eligible for study participation.  The 
Investigator must not prescribe or administer the study drug until the patient has completed 
registration and has been approved to participate in the study. 
No randomization will be done for Parts 1 and 2 as patients will all receive NOX66 and EBRT 
treatment.  Therefore, patients will be enrolled sequentially in dose cohorts of Part 1 and in 
parallel for Part 2. 
The clinical site will be assigned a unique 4-digit number and each patient will be assigned a 
unique screening number after written informed consent is obtained.  Each patient will have a 
unique identifier (6-digit number [XXXX-YY]) that combines both the site (XXXX) and 
screening number (YY).  Participant numbers will be assigned sequentially at the clinical site. 


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6.4 Study Drug Compliance 
NOX66 is packaged with each suppository individually sealed in plastic packaging and boxed as 
quantities to meet the treatment needs.  The study drug is to be stored refrigerated (2°C to 8°C 
[35.6°F to 46.4°F]). 
The suppository units are packed in individually sealed PVC suppository packaging shells and 
boxed in appropriate quantities.  Label information for the primary packaging will include, but 
are not limited to the study number, name of the product, lot number, route of administration and 
Sponsor name. 
Label information for the secondary package box which contains the suppository units will 
include but are not limited to the Sponsor’s name and address, study number, name of the 
product, lot number, re-assay date, storage conditions, dosage and patient identifier. 
All dosages of NOX66 will be self-administered by the study patients or administered by a 
caregiver.  A missed dose should be taken as soon as it is noted if it has not been longer than 
2 hours.  If the period exceeds 2 hours, the missed dose should be skipped. 
When patients are dosed at the site (Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 and 3), 
they must bring the study drug received at the start of the treatment cycle to the study site and 
will administer the study drug under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents, eCRF and Patient Study 
Drug Administration Diary for treatment compliance.  The dose of study drug and study patient 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study drug. 
When NOX66 is self-administered by the patients or administered by their care giver at home 
(all dosing days except the mornings of Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3), compliance with study drug will be assessed at each visit.  The patient or care giver 
should use gloves for drug administration.  Compliance will be assessed by direct questioning 
and counting returned unused suppositories during the site visits and documented in the source 
documents and eCRF.  Patients will also receive a Patient Study Drug Administration Diary in 
which they must record details of each dosing (e.g., date and time of dosing, number of 
suppositories, missed doses).  Deviation(s) from the prescribed dosage regimen should be 
recorded in the eCRF. 
A record of the number of NOX66 suppositories dispensed to and taken by each patient must be 
maintained and reconciled with study drug and compliance records for each cycle.  Actual drug 


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start and stop dates, including dates for drug delays and/or dose reductions will also be recorded 
in the eCRF. 
6.5 Concomitant Therapy 
Any medication (e.g., ADT [for mCRPC patients], bisphosphonates or denosumab, pain 
medication) or vaccine (including COVID-19 vaccine, over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the patient is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor.  Please see Sections 8.2.2.4.1 and 8.2.2.4.2, respectively, 
for details on permitted and prohibited medications. 
6.6 Dose Modification 
In patients who develop significant toxicity determined to be related to NOX66 after Cycle 1, the 
Investigator may reduce the number of suppositories or the daily dose for the patient to remain in 
the study (Table 6-2). 
In the first occurrence of any AE > Grade 1 due to NOX66 (excluding Grades 1 and 2 
anal/perianal rash), NOX66 treatment will be put on hold until the AE resolves to Grade 1 after 
which dosing can be restarted with the same dose level.  If the AE occurs again, NOX66 
treatment should be put on hold until the AE resolves to Grade 1 after which dosing may be 
restarted with a lower dose, i.e., reduced number of suppositories (Table 6-3).  Grades 1 and 2 
anal/perianal rash should be managed with hydrocortisone cream; no treatment hold is required 
in these cases. 


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Table 6-2 
Dose Modification of Study Treatment NOX66 
Current Dose 
Dose Reduction 
Total Daily Dose 
Number of 
Suppositories/Day 
Total Daily Dose 
Number of 
Suppositories/Day 
800 mg 
(400 mg BID) 
2 
400 mg 
(once daily) 
1* 
1200 mg 
(600 mg BID) 
2 
600 mg 
(once daily) 
1* 
1600 mg 
(800 mg BID  
[2× 400 mg per 
administration]) 
4 
800 mg 
(400 mg BID) 
2 
2400 mg 
(1200 mg BID 
[2 × 600 mg per 
administration]) 
4 
1200 mg 
(600 mg BID) 
2 
BID = twice daily 
* To be administered during evening dosing. 
Table 6-3 
Management of NOX66 Treatment-related Toxicity 
Event (NCI-CTCAE v5.0) 
Action 
Grades 1 to 2 toxicity  
(all events) 
Investigator judgement to continue treatment or interrupt dose (maximum 
28 days), except for Day 1 of a new cycle of study treatment, as described above.  
Initiate optimal supportive care and causality investigation.  Consider resuming at 
the same dose level when toxicity has resolved or is resolving with prophylactic 
treatment (if appropriate).  If toxicity recurs on rechallenge and does not resolve 
in < 7 days despite optimal supportive care, consider a dose reduction. 
Grade 3 to 4 toxicity 
(1st event) 
Interrupt study treatment and initiate optimal supportive care and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity has 
resolved or is resolving with prophylactic treatment (Grade ≤ 2 or returns to 
baseline), consider restarting NOX66 with reduced number of suppositories per 
day and prophylactic treatment (if appropriate). 
Grade 3 toxicity 
(recurrence of the same AE) 
Interrupt study treatment and initiate optimal supportive case and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity has 
resolved or is resolving (Grade ≤1 or returns to baseline), consider restarting 
NOX66 with reduced number of suppositories per day and prophylactic treatment 
(if appropriate).  After 2 dose reductions, consider permanent discontinuation of 
NOX66 for Grade 3 events. 
Grade 4 toxicity 
(recurrence of the same AE) 
Patients should permanently discontinue NOX66 treatment. 
AE = adverse event; NCI-CTCAE = national cancer Institute-Common Terminology Criteria for Adverse Events 
 
If a perineal and/or anal rash develops (Grade 1 to 2), a topical hydrocortisone containing 
hemorrhoid cream/ointment and/or cutaneous cream should be used.  For Grade 3 to 4 perineal 
and/or anal rash, NOX66 treatment should be delayed until the rash has resolved to Grade 1 or 
completely and hydrocortisone cream should be used as appropriate.  NOX66 should also be 


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delayed if there is proctitis, rectal mucositis or an ulcer of Grade 2 or higher.  Treatment may be 
resumed when toxicity has decreased to Grade 1.  Treatment with NOX66 should also be delayed 
in the presence of anorectal infections and may be resumed after they are resolved.  See also 
Section 7.1.1 for details on handling of dose delays. 
6.6.1 
Dose Modification of Radiotherapy 
The Investigator may adjust the dose of radiotherapy based on the standard operating procedure 
(SOP) of the site if the patient experiences intolerance or severe toxicity to radiotherapy during 
the study period. 
Patients who are eligible for an additional course of radiotherapy to the same or other lesion due 
to chronic pain or new symptomatic lesion (not related to progression) may receive an additional 
course of EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively).  If such a 
case occurs, it should be discussed with the Medical Monitor before administration of the 
additional course. 
6.7 Study Drug After the End of the Study 
All patients will receive NOX66 treatment from Cycle 1 until disease progression, unacceptable 
toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by 
the Investigator or termination of the study by Sponsor.  The entire study will finish when the 
last patient enrolled in Part 2 completes 6 months treatment.  All patients receiving study drug at 
that time will be switched to the NOX66 compassionate access program.  Those patients on the 
compassionate access program will continue to receive NOX66 treatment until disease 
progression or unacceptable toxicity.  These patients will be followed until death, or the patient 
is lost to follow-up. 
7 Discontinuation of Study Drug and Participant Discontinuation 
7.1 Discontinuation of Study Drug 
7.1.1 
Safety Stopping Criteria:  
It may be necessary for a patient to permanently discontinue (definitive discontinuation) study 
drug.  If study drug is definitively discontinued, the patient will remain in the study to be 
evaluated for clinical observation and safety monitoring.  See the SoA (Table 1-1 [Parts 1 and 2]) 
for data to be collected at the time of discontinuation of study drug and follow-up and for any 
further evaluations that need to be completed. 


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Patients may be discontinued from study drug in the following situations: 
• 
Patient decision.  The patient free to discontinue study drug at any time, without prejudice to 
further treatment. 
• 
Any AE that in the opinion of the Investigator or Sponsor contraindicates dosing or meets the 
criteria for discontinuation. 
• 
Recurrence of the same Grade 3 AE, even if recurrence is at a lower dose of study drug, with 
the exemption of localized skin reactions associated with drug administration which responds 
to topical corticosteroids. 
• 
Unacceptable toxicity. 
• 
Severe noncompliance with the protocol. 
• 
Disease progression or unacceptable toxicity. 
• 
Patient started alternative anticancer therapy including another investigational agent. 
• 
Patient is lost to follow-up. 
For patients with mCRPC, study drug will not be stopped due to rises in PSA alone.  The 
Prostate Cancer Working Group 3 (PCWG-3) emphasized the importance of keeping patients on 
the study until radiographic or symptomatic progression, which better reflects the clinical course. 
7.1.1.1 
Temporary Discontinuation 
Study drug administration may be stopped temporarily (up to 21 days) due to AE(s) and will be 
restarted after the AE resolves to Grade 1.  If an AE has not resolved after this period, but the 
Investigator confirms there is clinical benefit for the patient to continue study participation, this 
period could be extended upon discussion with Medical Monitor and Sponsor.  If the AE still has 
not resolved after this extended period, and no clinical benefit was confirmed then the patient 
will be discontinued from study drug. 
7.1.2 
Dose Escalation Rules and Safety Steering Committee 
A dose in which the safety stopping criteria have been met (Section 7.1.1) or where toxicity was 
observed based on the DLT assessment criteria (Section 7.1.2.2) will not be repeated and further 
dose escalation will not occur.  Where stopping criteria have not been met, the decision of the 
SSC may be to give the next intended dose, a smaller than the predefined dose increment, a 
repeated dose or to stop dosing.  There will be a temporary halt for enrollment after the first 
3 patients are enrolled in each cohort until the SSC clears that the dose level is safe to continue 
the dose escalation. 


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Measures to ensure data integrity and safety of patients will be detailed in the Data and Safety 
Monitoring Plan. 
If the Investigator, the Medical Monitor or the Sponsor becomes aware of conditions or events 
that suggest a possible hazard to patients if the clinical study continues, then the clinical study 
may be terminated after appropriate consultation among the involved parties.  The clinical study 
may be terminated at the Sponsor’s discretion also in the absence of such a finding. 
Should the study be terminated, and/or the study center closed for whatever reason, all 
documentation pertaining to the study and study drug must be returned to Sponsor.  Any actions 
of the study site required for assessing or maintaining patient safety will continue as required, 
despite termination of the study by the Sponsor. 
7.1.2.1 
Safety Steering Committee 
The safety of the patients enrolled in this study will be closely monitored on an ongoing basis by 
an SSC during dose escalation review meetings.  The SSC will review clinical data from the 
study, including safety, available efficacy and PK data (if available), and will ensure the 
appropriate selection of doses to be used in the dose escalation and dose expansion phases of the 
study.  All safety data collected up to Cycle 1 Day 21 for each patient will be reviewed. 
The SSC will consist of: 
• 
The Sponsor’s Study Team Physician or a designee. 
• 
Clinical Research Organization’s Medical Monitor, who will chair the committee. 
• 
The Investigators or a designee from every participating site, at least from sites which enroll 
patients in the respective dose cohort. 
• 
Other Sponsor and Parexel team members. 
The SSC charter will define the exact membership and who should be present for 
recommendations to be made. 
For the initiation of a new dose level, the SSC will evaluate the available safety, tolerability and 
PK data (if available) of NOX66 in combination with EBRT.  Once 3 patients have completed 
their DLT assessment period, the SSC will review and assess all available safety data to make 
recommendations regarding that dose and/or the next dose/study part.  The decisions and 
decision-making regarding the next dose level will be documented and provided to the 
Investigators prior to dosing of new patients.  The final decision regarding dose escalation or 
dose de-escalation will be made by the SSC. 


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The SSC will be responsible for the following: 
• 
Assessment of all available safety, tolerability and exposure data during the study. 
• 
Defining patients who have experienced a DLT per protocol definitions of DLT (see 
Section 7.1.2.2). 
• 
All recommendations regarding dose escalation or dose de-escalation of NOX66.  The SSC 
may recommend proceeding with dose escalation, expand the current dose level with 
additional patient enrollment or de-escalate the dose to a lower dose level. 
• 
All recommendations regarding modification of NOX66 dosing schedule, if required.  The 
SSC may recommend adjusting the NOX66 dose, dosing frequency or schedule during either 
Cycle 1 or subsequent cycles.  In this situation, the protocol must be amended. 
• 
All recommendations relating to initiation of Part 2 enrollment. 
• 
Recommendation for cessation of dose escalation. 
• 
The review of safety and tolerability of both doses of EBRT (8 Gy and 20/25 Gy 
administered as 1 or 5 fractionated doses). 
• 
All recommendations regarding the replacement of any excluded or withdrawn patients on 
study, if necessary.* 
* Any patient initiated on treatment in error (i.e., because he or she failed to meet inclusion 
and/or exclusion criteria) but meeting the criteria of an evaluable patient, will be reviewed on a 
case-by-case basis by the SSC to determine if the patient should be included or excluded in the 
recommendation for dose escalation. 
See Section 7.1.2.2 for details on DLT assessment. 
7.1.2.2 
Assessment of Dose-limiting Toxicities 
A DLT is defined as an AE that occurs during Cycle 1 (Day 1 to Day 21) that is assessed as 
unrelated to the disease, intercurrent illness or concomitant medications and that, despite optimal 
therapeutic interventions, meets any of the following criteria (judged to be associated with 
NOX66 alone or in combination with EBRT [possibly, probably or definitely related to]): 
1. Grade 3 or higher non-hematological toxicities (excluding alopecia) with the following 
exceptions: 
a. Grade 3 nausea/vomiting or diarrhea < 72 hours with adequate antiemetic and other 
supportive care 


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b. Grade 3 fatigue < 1 week 
c. Grade 3 or higher electrolyte abnormality that lasts 24 to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical drugs 
2. Grade 4 non-hematologic (non-laboratory) toxicity of any duration. 
3. Grade 3 or Grade 4 febrile neutropenia of any duration. 
4. Grade 4 neutropenia or thrombocytopenia > 5 days. 
5. Grade 3 thrombocytopenia with bleeding. 
6. Grade 3 thrombocytopenia in combination with a Grade 3 or greater blood and lymphatic 
system disorder. 
7. Grade 3 AST or ALT that is associated with a Grade 2 or greater rise in bilirubin that lasted 
for more than 7 days. 
8. Any AST or ALT > 8 × ULN regardless of duration (5 to 8 × ULN for up to 2 weeks is 
allowed). 
9. Any AE that results in a treatment delay or hold of > 14 days. 
Grading of DLTs will follow the guidelines provided by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. 
All AEs of the grades specified above count as DLTs unless they are clearly and incontrovertibly 
due to disease progression or extraneous causes. 
After all patients enrolled in a cohort complete Cycle 1, and the data from these patients are 
available, a dose escalation meeting will be conducted.  At least 3 evaluable patients are required 
in order to proceed with DLT evaluation for each cohort. 
The criteria for determination of an evaluable patient for a dose escalation decision or 
determination of the MTD, must include: 
• 
Patient who experienced a DLT during the 21-day treatment cycle (Cycle 1), or 
• 
Patient who has not experienced a DLT and has taken at least 80% of the prescribed daily 
doses of NOX66 and completed all safety evaluations. 
For each dose escalation cohort, additional patients may be enrolled or replaced if a patient 
discontinues prior to the completion of Cycle 1 for reasons other than safety.  Patients who 
develop a DLT and discontinue treatment will not be replaced. 


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If a patient develops any DLT during Cycles 2 to 6, these will be considered ‘DLT equivalent 
toxicity’ and will be recorded in the eCRF.  This information may be considered during SSC 
review to assess dose escalation. 
When a DLT occurs, the site must immediately inform Parexel who will then inform the other 
sites that a DLT has occurred and evaluate if a second DLT has occurred at any other sites. 
Assessment of toxicities and decisions about dose recommendation for Part 1 (dose escalation) 
will be made during the SSC meeting. 
7.2 Participant Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral or administrative reasons.  
The patient will be definitively discontinued from both the study drug and from the study at that 
time. 
The primary reason for a patient withdrawing prematurely should be recorded in the patient’s 
source records and on the eCRF.  In the absence of a medical contraindication or significant 
protocol violation, every effort will be made by the Investigator to keep the patient in the study.  
Patients who discontinue study drug because of an AE but agree to participate with any 
follow-up assessments will undergo the EOT/ED Visit and will be requested to return for the 
Follow-up Visits.  The Investigator must contact the Medical Monitor promptly when deciding if 
a patient should be withdrawn or if the patient elects to stop the study. 
Patients withdrawn from this study cannot re-enroll.  Patients who discontinue for a non-safety 
related reason may be replaced if the patient is withdrawn during Cycle 1 in Part 1.  Withdrawal 
of consent must be ascertained and documented by the Principal Investigator who must consult 
with the Medical Monitor and document the withdrawal of consent in the eCRF and in the 
medical records.  Patients will be asked about the reason(s) for withdrawal and the presence of 
any AEs.  Should the patient agree to be followed for safety information, this should be 
documented in the medical records. 
Patients experiencing adverse reactions should be followed until the AE has resolved, stabilized 
or is no longer deemed clinically significant, as judged by the Investigator.  Appropriate 
supportive and/or definitive therapy will be administered as required. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 


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If a patient withdraws from the study, he or she may request destruction of any samples taken 
and not tested and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA.  Refer to the SoA (Table 1-1 [Parts 1 and 2]) for data to be 
collected at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
7.3 Loss of Participants to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the patient on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the 
patient wishes to and/or should continue in the study. 
• 
In cases in which the patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (where possible, three telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the patient’s medical 
record/eCRF. 
• 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1 [Parts 1 and 2]).  
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study drug. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 


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All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The Investigator will maintain a Screening Log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be utilized for Screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
Repeat or unscheduled samples may be taken for safety reasons. 
8.1 Efficacy Assessments 
Efficacy will be assessed by evaluating the change from baseline PSA for patients with mCRPC 
(Section 8.1.1).  For all patients, DCR (as measured by complete response [CR], PR and SD; 
Section 8.1.2) will also be evaluated based on change from baseline imaging using RECIST v1.1 
criteria.  In mCRPC patients, bone lesions will be evaluated using PCWG-3 criteria 
(Section 8.1.3).  Other assessments to be performed during this study are ECOG scores, pain 
severity (Section 8.1.4), morphine and analgesic use (Section 8.1.6) and change from baseline 
Patient Reported Outcomes (PROs) using the questionnaires listed in Section 8.1.5 for all 
patients enrolled in the study. 
Efficacy will also be assessed by looking at the skeletal-related events (SREs) and symptomatic 
skeletal events (SSEs) (Section 8.1.7), progression-free survival (PFS; Section 8.1.8), overall 
survival (OS; Section 8.1.9), and overall or objective response rate (ORR; Section 8.1.10). 
8.1.1 
Prostate-specific Antigen (PSA) Response and Progression (mCRPC 
only) 
Blood for PSA assessment will be collected during Screening, on Day 1 of Cycles 1 to 5, every 
second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at the 6-, 9- and 
12-month Follow-up Visits for all patients including those who discontinue the study for any 
reason other than disease progression (Table 1-1 [Parts 1 and 2]).  Patients who discontinue the 
study drug for reasons other than disease progression will continue to have PSA evaluated until 
disease progression, withdrawal of consent, initiation of new anticancer therapy, the end of the 
12-month follow-up period or death, whichever comes first.  Patients who discontinue the study 


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drug due to disease progression do not need to provide PSA samples during the Follow-up Visits.  
PSA will be used as a blood-based biomarker for tracking and monitoring the response state 
during the study for mCRPC. 
A PSA response will be considered as a PSA value reduction ≥ 30% from baseline at the end of 
Cycles 3 and 6.  A PSA response reduction from baseline at any time point will also be assessed 
as a secondary objective. 
According to PCWG-3, a sequence of rising PSA values should be obtained at a minimum of 
1-week intervals with a starting value of 2.0 ng/mL.  PSA PFS is the time from first dose 
administration to PSA progression or death. 
8.1.2 
Disease Control Rate 
Disease control rate is measured by the percentage of patients with a best overall confirmed 
response of CR or PR at any time plus SD from first dose administration until disease 
progression or death due to any cause or the start of new anticancer therapy.  CR, PR plus SD 
will be assessed based on RECIST v1.1 (Table 1-1 [Parts 1 and 2]). 
8.1.3 
Tumor Imaging Assessment 
In this study, the preferred assessment of soft tissue lesions is CT or MRI scans using 
RECIST v1.1 criteria and the preferred assessment method for bone lesions is bone scan using 
PCWG-3.   
Tumor imaging using RECIST v1.1 and PCWG-3 criteria will be performed during within 
28 days prior to enrollment, every 8 weeks (± 7 days) from the first study dose administration up 
to Week 26, and every 12 weeks (± 7 days) thereafter until disease progression (as defined by 
RECIST v1.1 and PCWG-3 criteria), withdrawal of consent, initiation of new anticancer therapy 
or death.  Tumor imaging should ideally be performed during the rest period before the start of 
the next treatment cycle. 
• 
If a patient permanently discontinues the study drug due to disease progression according to 
RECIST v1.1 criteria, a tumor imaging and disease response assessment is not required. 
• 
If a patient permanently discontinues the study drug due to clinical disease progression, a 
tumor imaging and disease response assessment does not need to be repeated if completed 
≤ 28 days after the last dose of study drug. 
For patients who permanently discontinue study drug for any reason other than confirmed 
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performed every 12 weeks (± 7 days) for up to 12 months after the last dose of the study drug 
until disease progression, withdrawal of consent, initiation of new anticancer therapy, the patient 
is lost to follow-up or death, whichever comes first. 
• 
If a patient meets disease progression during the follow-up period according to RECIST v1.1 
criteria, a tumor imaging and disease response assessment is not required. 
• 
If a patient meets clinical disease progression during the follow-up period, a tumor imaging 
and disease response assessment does not need to be repeated if completed ≤ 28 days after 
the date of clinical disease progression. 
For patients who permanently discontinue the study drug or the follow-up period due to 
withdrawal of consent, the Investigator is to obtain tumor imaging and conduct a disease 
assessment at the time of the ED Visit or final Follow-up Visit if the patient agrees.  A tumor 
imaging and disease response assessment does not need to be repeated if completed ≤ 28 days of 
the date of withdrawal of consent. 
The same imaging method should be used for a patient throughout the study and images should 
be read on site.  In Part 2 of the study, images should read on site and also be submitted in digital 
format to a Central Imaging Provider as detailed in the Investigator Site Operations Manual. 
Baseline scans shall be assessed and any lesions which can be measured in accordance with 
RECIST v1.1 or PCWG-3 (CT or MRI) criteria will be noted as “target lesions”.  Target 
measurable lesions may either be at the site of irradiation or non-irradiation and the number of 
lesions will be capped at 10 lesions (for RECIST v1.1).  Patients with identified measurable 
target lesions will be assessed for overall response using RECIST v1.1 criteria.  In addition to 
RECIST v1.1, all measurable lesions (irradiated and non-irradiated) will be measured and 
monitored for change (including new lesions).  To identify abscopal responses, all lesions will be 
evaluated. 
At a minimum, imaging of the chest, abdomen and pelvis should be performed using consistent 
imaging modality (CT or MRI).  Any other areas of disease involvement should be additionally 
investigated based on the signs and symptoms of individual patients.  During the assessments, 
subsequent to baseline, any other sites at which new disease is suspected should also be 
appropriately imaged. 


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Bone scans will be used for qualitative evaluation of lesions and quantitative evaluation of new 
and/or resolved lesions.  Bone scans will be assessed using PCWG-3 criteria. 
The RECIST v1.1 and PCWG-3 guidelines for measurable, non-measurable, target and non-
target lesions and the objective tumor response criteria are presented in Section 10.5. 
8.1.4 
Eastern Cooperative Oncology Group Performance Status Score 
Eastern Cooperative Oncology Group Performance Status Score5 will be evaluated by the 
Investigator at Screening, Day 1 of Cycles 1 to 3, every second cycle thereafter (i.e., Cycles 5, 7, 
9, 11 etc.) and the EOT/ED Visit (Table 1-1 [Parts 1 and 2]).  The assessment should be 
performed by the same Investigator throughout the study, whenever possible. 
Table 8-1 
Eastern Cooperative Oncology Group Performance Status Score 
Grade 
ECOG Performance Score 
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 our work of a light 
or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to a bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry out any selfcare.  Totally confined to a bed or chair. 
5 
Dead 
 
8.1.5 
Clinical Outcome Assessment 
A Clinical Outcome Assessment is any assessment that may be influenced by human choices, 
judgement or motivation and may support either direct or indirect evidence of treatment benefit.  
Patient reported outcome is one of these types of Clinical Outcome Assessments. 
Patient reported outcome, an umbrella term referring to all outcomes and symptoms, are directly 
reported by the patient.  Patient reported outcomes have become a significant endpoint when 
evaluating effectiveness of treatments in clinical trials. 
Questionnaires are to be completed before any other study assessments performed on the day of 
the visit. 


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The following PRO instruments will be administered for analysis of the PRO endpoints in this 
study: 
• 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire for Cancer Patients (EORTC-QLQ-C30) 
The EORTC-QLQ-C30 is a well-established PRO questionnaire developed to monitor 
health-related Quality of Life (QoL) outcomes among cancer patients (Section 10.6).  The 
questionnaire assesses important functioning domains (e.g., physical, emotional, social) and 
common cancer symptoms (e.g., fatigue, pain, nausea, vomiting, appetite loss).  The 
questionnaire will be completed at Screening, on Day 1 of Cycles 3 and 5, followed by every 
4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 
and 2]). 
• 
Brief Pain Inventory – Short Form (BPI-SF) 
Worst pain, general pain and pain’s interference with daily life will be assessed during the 
study drug using the BPI-SF (Section 10.7).  The questionnaire will be completed at 
Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles thereafter (e.g., Cycle 9, 
Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 and 2]).  The BPI-SF comprises a 
total of 15 items measuring 2 domains: pain severity and pain interference.  Items measuring 
pain severity (including ‘worst pain’) are rated on an 11-point numeric rating scale ranging 
from 0=No pain to 10=Pain as bad as you can imagine.  All BPI-SF items are measured using 
a 24-hour recall period. 
• 
Functional Assessment of Cancer Therapy – Prostate (FACT-P) 
The FACT-P questionnaire is a relevant, worldwide tool used for assessing the health-related 
QoL in men with prostate cancer.  The FACT-P is a 39-item questionnaire composed of the 
FACT-General (FACT-G) original subscales (Physical Well-being, Social/Family Well-being, 
Emotional Well-being and Functional Well-being) and a Prostate Cancer Subscale 
(Section 10.9).  Each item is rated on a 5-point scale ranging from 0 (not at all) to 4 (very 
much).  A higher score indicates a better QoL.  The questionnaire will be completed by 
mCRPC patients only at Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles 
thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 and 2]). 
• 
Patient Experience Questionnaire (PEQ) 
The Sponsor has developed a questionnaire to evaluate the patient’s experience with the 
suppository dosage form (Section 10.8). 
The PEQ will be completed on Day 2 of Cycle 1, Day 1 of Cycle 3 and at the EOT/ED Visit 
(Table 1-1 [Parts 1 and 2]). 


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8.1.6 
Morphine Administration and Analgesic Use 
The dose and frequency of morphine administration and analgesic use will be assessed at each 
on-site study visit based on the patient’s concomitant medication use assessment. 
8.1.7 
Skeletal-related Events and Symptomatic Skeletal Events Assessment 
Skeletal-related events and SSEs will be evaluated based on the patient’s clinical history and 
examinations, including but not limited to incidence of fractures and pain.  Assessments will be 
performed at each on-site study visit. 
8.1.8 
Progression-free Survival 
Progression-free survival is defined as the duration of time from first dose administration to date 
of disease progression is objectively documented, including tumor progression, early 
discontinuation or death prior to data cut-off.  Patients alive and progression-free at the time of 
data cut-off will be censored at the date last known alive.  Progression-free survival will be 
assessed every 8 weeks (± 7 days) from the first dose administration up to Week 26, and every 
12 weeks (± 7 days) thereafter until disease progression according to RECIST v1.1 criteria. 
8.1.9 
Overall Survival 
Overall survival is defined as time from the date of first dose administration to date of death due 
to any cause.  Patients alive at the time of data cut-off will be censored at date last known alive. 
8.1.10 Overall or Objective Response Rate 
Response rate is defined as the proportion of patients who have confirmed CR or PR by objective 
disease progression RECIST v1.1, as assessed by the Investigator/local radiologist.  Overall or 
ORR will be assessed every 8 weeks (± 7 days) from the first dose administration up to Week 26, 
and every 12 weeks (± 7 days) thereafter until disease progression. 
Complete response is defined when all target lesions present at baseline have disappeared (with 
the exception of lymph nodes which must be < 10 mm to be considered nonpathological) and no 
new lesions have developed since baseline.  A visit response of PR is defined when the sum of 
diameters of the target lesions has decreased by 30% or more compared to baseline (with no 
evidence of progression). 


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8.2 Safety Assessments 
8.2.1 
Administrative Procedures 
8.2.1.1 
Informed Consent 
Informed consent must be documented according to Section 10.1.3.  
8.2.1.2 
Participant Identification Card 
All patients will be given a patient identification card identifying them as participants in a 
research study.  The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency.  The Investigator or qualified designee will 
provide the patient with a patient identification card immediately after the patient provides 
written informed consent. 
The patient identification card also contains contact information so that a healthcare provider can 
obtain information about study drug in emergency situations where the Investigator is not 
available.  At the time of enrollment/study drug allocation, site personnel will add the study drug 
dosage to the patient identification card. 
8.2.2 
Screening and Eligibility Assessments 
8.2.2.1 
Eligibility Criteria 
All inclusion and exclusion criteria (Section 5.1 and Section 5.2) will be reviewed by the 
Investigator or designee to ensure that the patient qualifies for the study.  Review of eligibility 
criteria will be done at Screening and at the Day -1 visit. 
8.2.2.2 
Participant Demographics and Baseline Characteristics 
Demographic data will be collected including age (at the day of Screening), gender, race, 
ethnicity and baseline characteristics (e.g., tobacco and smoking history, alcohol consumption 
history) as allowed by the local regulations. 
8.2.2.3 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at Screening.  The 
medical history will collect all active and chronic conditions from each patient.  Gleason score 
will be collected as part of the medical history for patients with mCRPC only.  Details regarding 
the disease for which the patient has enrolled in this study will be recorded separately and not 


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listed as medical history.  If the patient has data available from any historical genetic assays 
conducted to identify genetic variations, this will also be collected (all patients). 
8.2.2.4 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the patient within 30 days prior to the Screening Visit. 
The Investigator or qualified designee will record medication, if any, taken by the patient during 
the study through the last visit.  Concomitant medications will be recorded for 30 days after the 
last dose of study drug (or longer if related to an SAE). 
8.2.2.4.1 
Permitted Medications 
Analgesic agents, ADT, bisphosphonates and denosumab are allowed to be used during the 
study.  The Investigator or qualified designee will review the use of analgesic agents taken by the 
patient as part of the concomitant medications review (see SoA [Table 1-1 (Parts 1 and 2)]). 
Anti-microbial agents to control infections (e.g., urinary tract infection) are allowed as per SOC 
guidelines. 
Topical hydrocortisone-containing hemorrhoid cream/ointment and/or cutaneous cream is 
allowed for the treatment of a perineal and/or anal rash and can be administered straight after 
study drug administration, and as frequently as required as per institution. 
The use of a small amount of water-soluble lubricant is advised before rectal administration.  No 
oil- or wax-based lubricants should be used during rectal administration. 
8.2.2.4.2 
Prohibited Medication 
The following medications and therapies are not allowed during the study: 
• 
Any concomitant chemotherapy. 
• 
Oral or parenteral glucocorticoids and herbs known to alter PSA levels. 
• 
Other investigational agents. 
• 
Inducers (phenobarbital) and inhibitors (valproic acid, probenecid, atazanavir, gemfibrozil, 
indinavir) of phase 2 drug metabolizing enzymes are prohibited within 14 days prior to first 
dose of NOX66 and the rest of the study. 


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• 
Based on in vitro data, idronoxil may inhibit the activity of cytochrome P450 (CYP) 2C8, 
CYP2C9, CYP2C19 and CYP3A4 enzymes in human microsomes in a range of 0.457 to 
3000 µM and concomitant medication that is metabolized by these enzymes should be used 
with caution. 
• 
The use of inhibitors of uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes should 
be avoided. 
• 
Soya contains a high proportion of isoflavones which may interfere with the bioanalytical 
assay used for detection of idronoxil (active substance), itself an isoflavone derivative, in 
plasma and urine samples, thus within 2 days prior to NOX66 administration and for the 
entire duration of the first cycle of the study, patients must be on a soya free diet.  The 
following types of foods are prohibited: edamame, meat alternatives, miso, soymilk, soy 
nuts, soy sauce (tamari, shoyu and teriyaki), tempeh, and textured soy protein.  Trace or very 
small amounts of soy in foods are permitted. 
8.2.2.5 
Calibration of Equipment 
The Investigator (or qualified designee) is responsible for ensuring that any device or instrument 
used for a clinical evaluation/test during the study that provides information about eligibility 
criteria and/or safety or efficacy parameters is suitably calibrated and/or maintained to ensure 
that the data obtained are reliable and/or reproducible.  Documentation of equipment calibration 
must be retained as source documentation at the study site. 
8.2.3 
Dose-limiting Toxicity 
See Section 7.1.2.2 for details. 
8.2.4 
Physical Examinations 
A complete physical examination will be performed at Screening.  A symptom-directed physical 
examination will be performed prior to the first dose of study drug in Cycles 1 to 3, and every 
second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.; or within 3 days before Day 1 of the cycle) 
and at the EOT/ED Visit.  Physical examinations will include, at a minimum, assessments of the 
head, eyes, ears and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, endocrine systems and 
perineal and anal region.  Physical examinations need to include the assessment of the perineal 
and anal region.  Height will be recorded at Screening only.  Weight will be measured at 
Screening, Cycles 2 and 5 and every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.). 


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Abbreviated physical examinations may be conducted as needed and will focus on new 
symptoms and will include examination of relevant systems as identified by the Investigator. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.5 
Vital Signs 
Vital signs will be assessed as specified in the SoA (Table 1-1 [Parts 1 and 2]). 
Oral or tympanic (both are acceptable) temperature, pulse, respiratory rate and blood pressure 
(BP) will be assessed at Screening and during Cycle 1 at the following timepoints: predose and at 
1 and 4 hours postdose on Days 1, 6 and 14.  Vital signs will be measured predose on Day 1 of 
Cycles 1 to 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED 
Visit. 
Blood pressure and pulse measurements will be assessed supine with a completely automated 
device.  Manual techniques will be used only if an automated device is not available or to 
confirm automated readings, as needed. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
patient in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of one pulse and 
one BP measurement (after the patient has been supine for 5 minutes). 
8.2.6 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained in Parts 1 and 2 as outlined in the SoA (Table 1-1 
[Parts 1 and 2]) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT and QTc intervals. 
For all patients in Part 1 and the first 10 patients in each tumor type for Part 2 who will undergo 
PK sampling, a series of ECGs (in triplicate, within 1 to 2 minutes apart) will be collected at 
Screening, and at the following timepoints (Table 1-2):  
• 
Cycle 1: 
o Days 1, 6 and 14: predose (within 30 minutes prior to dosing to allow for sitting BP if 
needed) and at 1, 2, 3, 4 and 6 hours postdose (+ 15 minutes).  Additionally, for Part 1 
only, ECGs will also be taken on Day 1 at 8 and 12 hours postdose (+ 15 minutes). 
o Day 2: predose. 


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• 
Cycle 2 Day 1: Predose (within 30 minutes prior to dosing to allow for sitting BP if needed) 
and at 1 hour postdose (+ 15 minutes). 
• 
Cycle 3 Day 1: Predose (within 30 minutes prior to dosing to allow for sitting BP if needed) 
and at 1 hour postdose (+ 15 minutes). 
For patients in Part 2 who will not undergo PK sampling, a series of ECGs (in triplicate, within 1 
to 2 minutes apart) will be collected at Screening, and a single ECG predose (within 30 minutes 
prior to dosing to allow for sitting BP if needed) will be collected on Day 1 of Cycles 1 to 3. 
Electrocardiograms will be taken predose (within 30 minutes prior to dosing to allow for sitting 
blood pressure if needed) for all patients in both study parts on Day 1 of every second cycle 
thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit.  Electrocardiograms will be 
obtained after 5 minutes of rest in the supine position. 
Twelve-lead ECGs will be obtained after the patient has been resting supine for at least 
5 minutes prior to the times indicated in the SoA.  All ECGs should be recorded with the patient 
in the same physical position. 
At each time point at which triplicate ECG recordings are required, three individual ECG 
tracings should be obtained as closely as possible in succession, within 1 to 2 minutes apart.  The 
full set of triplicates should be completed in less than 4 minutes. 
8.2.7 
Clinical Safety Laboratory Assessments 
Refer to Section 10.2 for the list of clinical safety laboratory tests to be performed and to the 
SoA (Table 1-1 [Parts 1 and 2]) for the timing and frequency.  Clinical laboratory assessments 
will be done at Screening, Cycle 1 on Day 1 (or within 3 days before the first dose administration 
on Day 1), Days 6 and 14 (within 1 day before dose administration on each of Days 6 and 14), on 
Day 1 (or within 3 days of Day 1) of Cycles 2 and 3, every second cycle thereafter 
(i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
The Investigator must review the laboratory report, document this review and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  The 
laboratory reports must be filed with the source documents.  Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically abnormal during the study treatment period 
or within 30 days after the last dose of study drug should be repeated until the values return to 


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normal or baseline or are no longer considered clinically significant by the Investigator or 
Medical Monitor. 
• 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, where possible, and the Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Section 10.2 must be conducted 
in accordance with the laboratory manual and the SoA. 
• 
If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in patient management or 
are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or an 
AE or require dose modification), then the results must be recorded in the eCRF. 
8.2.8 
Radiotherapy Treatment Interruptions 
The frequency of radiotherapy treatment interruptions will be assessed by calculating the number 
of days of treatment interruptions over the study. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AE that are serious, considered related to the study drug or the study, or that caused the 
patient to discontinue the study drug or the study (see Section 7). 
Adverse event questioning will include specific questions regarding symptoms of COVID-19: 
fever, cough, dry throat, difficulty breathing and potential exposure in the past 2 weeks. 
Confirmed and suspected SARS-CoV-2 infection and COVID-19 will be recorded in the AE 
fields. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the last dose 
of study drug at the time points specified in the SoA (Table 1-1 [Parts 1 and 2]).  Follow-up of 
AEs/SAEs after the last dose of study drug will be done by phone call. 


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Medical occurrences that begin before the first dose administration but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3.  The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation.  However, if the Investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.3.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
The severity of AEs will be classified into Grade 1 through 5 using the NCI-CTCAE v5.0.  For 
details, refer to Section 10.3.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrence. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, until the 
event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Section 10.3) by the Investigator to the Sponsor of an 
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study drug under clinical investigation are met. 
The Sponsor and CRO have a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical investigation.  The 


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Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC), 
and Investigators. 
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with the 
IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
If a female patient or a female partner of a male study patient who has been exposed to the study 
drug becomes pregnant, the pregnancy and outcome of pregnancy should be monitored.  If a 
pregnancy in a female patient or a female partner of a male patient is reported, the Investigator 
should inform the Sponsor within 24 hours of learning of the pregnancy and should follow the 
procedures outlined in Section 10.4. 
Pregnancy of the female patient or of the male patient’s female partner alone is not regarded as 
an AE unless there is a suspicion that the study drug may have interfered with the effectiveness 
of a contraceptive medication.  Details of all pregnancies in female patients or female partners of 
male patients will be collected after the first dose administration and until 3 months after the last 
dose of NOX66.  Information on the pregnancy of a female patient or of the male patient’s 
female partner must be obtained directly from the female patient or the male patient’s female 
partner.  Therefore, prior to obtaining information on the pregnancy, the Investigator must obtain 
the consent of the female patient or the male patient’s female partner. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions.  Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE. 
8.3.6 
Cardiovascular and Death Events 
Not applicable. 


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8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable. 
8.3.8 
Adverse Events of Special Interest 
Not applicable. 
8.4 Treatment of Overdose 
For this study, any dose of NOX66 greater than 2400 mg within a 24-hour time period will be 
considered an overdose.  If a patient takes more doses than the assigned doses within a 24-hour 
time period, this will also be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for AE/SAE and laboratory abnormalities until resolved or for up 
to 30 days (whichever occurs first). 
3. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding whether the patient can continue the study will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.5 Pharmacokinetics 
In Parts 1 and 2, blood samples of approximately 4 mL each will be collected for measurement 
of plasma concentrations of idronoxil and selected metabolites as specified in the SoA (Table 1-1 
[Parts 1 and 2]).  For Part 2, PK sampling will only occur for the first 10 patients enrolled in each 
tumor group (mCRPC, BC and NSCLC).  A maximum of 31 samples will be collected at various 
time points during the study (see Table 1-3 for detailed sampling schedule) from each patient.  
Instructions for the collection and handling of PK samples will be provided in the laboratory 
manual.  The actual date and time (24-hour clock time) of each sample will be recorded in the 
eCRF.  If a bowel movement occurs during the collection period, the time of each bowel 
movement should be recorded, and the blood sample collections should continue as planned.  


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Plasma will be analyzed for the quantification of idronoxil and selected metabolites using a 
validated high-performance liquid chromatography and mass spectrometry methodology. 
Each plasma sample will be divided into 3 aliquots (1 each for PK, other analyses, and a 
back-up) and stored according to the instructions in the Laboratory Manual.  Samples collected 
for analyses of idronoxil plasma concentration may also be used to evaluate safety or efficacy 
aspects that address concerns arising during or after the study.  Pharmacokinetic parameters of 
idronoxil and selected metabolites will be determined by non-compartmental analysis.  
Pharmacokinetic sample analysis will be performed at a designated central laboratory. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files. 
8.6 Pharmacodynamics 
Please refer to Section 8.8 Biomarkers. 
8.7 Genetics 
The study will collect data from any available historical genetic assays conducted to identify 
genetic variations as part of the patients’ medical history. 
8.8 Biomarkers 
Changes from baseline in the lipidomic profile, plasma levels of cytokines, chemokines (all sites) 
and circulatory tumor deoxyribonucleic acid (ctDNA; for all patients at pre-selected sites that 
have peripheral blood mononuclear cell isolation capabilities in Australia and the US only) will 
be assessed (Parts 1 and 2).  These sample analyses will be performed at a designated central 
laboratory.  In addition, lipidomic profiling, capturing over 300 lipid species, will be determined 
by liquid chromatography-tandem mass spectrometry on the plasma samples collected from the 
study patients.  Samples for ctDNA analysis will not be collected from patients at sites in 
countries where this is not permitted by the regulatory authorities. 
Blood samples of approximately 4 mL each will be collected for measurement of plasma 
cytokine, chemokine and lipid concentrations and approximately 10 mL each for ctDNA analysis 
as specified in Table 1-4. 
Sampling for biomarker analysis will be performed at: 
• 
Screening or Cycle 1 on Days 1 and 15 


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• 
Prior to Cycle 3 Day 1: This sample should be collected after the patient has completed 
7 days of NOX66 treatment in Cycle 2, but before Day 1 of Cycle 3. 
• 
EOT/ED Visit. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Each plasma sample will be divided into 3 aliquots (1 each for PD, other analyses, and a 
back-up) and stored according to the instructions in the Laboratory Manual. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last patient’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to NOX66. 
If there is any remaining plasma from these samples, the Sponsor may perform additional 
analyses for relevant biomarkers in the future.  Taking part in this future research is optional.  
Patients will be asked to consent to their samples being used for this optional future research. 
8.9 Archival and Fresh Tissue Biopsy 
Patients will be asked whether they are willing to provide both archival and fresh tissue biopsy 
samples OR only fresh tissue biopsy if they do not have archival tissue samples.  Available 
archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  
Provision of a fresh biopsy sample and/or an archival tissue sample is optional.  See Table 1-5. 
8.10 Immunogenicity Assessments 
Immunoassays will not be performed during this study. 
8.11 Health Economics or Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
There will be no formal statistical hypotheses tested in this study.  All analyses will be 
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9.2 Sample Size Determination 
The primary objective of this study is to characterize the safety and tolerability of NOX66 and 
thereby inform the RP2D of NOX66 for future clinical studies in patients with mCRPC and other 
solid tumors.  Hence, for Part 1 and Part 2 the number of patients has been chosen with the aim 
to obtain adequate safety, tolerability, safety, PK, and PD profile data while exposing as few 
patients as possible to the study treatments and procedures. 
The sample sizes selected for this study are as follows: 
• 
Part 1 (Dose Escalation): Up to 30 patients will be enrolled in Part 1, in cohorts of 3 to 
6 patients (Dose Cohort 1) or 3 to 8 patients (Dose Cohorts 2 to 4) at each specified dose. 
• 
Part 2 (Dose Expansion): A total of 40 patients with mCRPC will be enrolled in Arm 1 and 
24 to 30 patients (12 to 15 patients per tumor type [BC and NSCLC]) will be enrolled in 
Arm 2.  The sample sizes for Part 2 were selected to provide sufficient observations for the 
estimation of endpoints and to assess any signal of efficacy following NOX66 and EBRT 
treatment. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Full Analysis Set (FAS) 
The FAS comprises all patients who received at least one dose of 
study drug. 
Safety Analysis Set 
The Safety Analysis Set consists of all patients who received at 
least one dose of study drug.  In this study, the Safety Analysis 
Set will be the same as the FAS. 
This analysis set will be the primary analysis set for all safety 
endpoints. 
Per Protocol Set (PPS) 
The PPS consists of all patients in the FAS with ≥ 80% treatment 
compliance and without major protocol deviations. 
PK Analysis Set 
The PK analysis set consists of all patients in the Safety Analysis 
Set and who have at least one idronoxil or metabolite plasma 
concentration value. 
Biomarker Analysis Set 
The Biomarker Analysis Set consists of all patients in the Safety 
Analysis Set and who have at least one plasma biomarker 
concentration value. 
 


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Separate summaries may be provided for patients participating in Parts 1 and 2. 
9.4 Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized prior to database lock.  Below 
is a description of planned statistical analyses.  Further details are presented in the SAP. 
9.4.1 
General Considerations 
The main aims of the study are to assess the safety, tolerability, efficacy, PK and PD profiles of 
idronoxil (and selected metabolites) and EBRT in combination with NOX66 in patients with 
prostate cancer and other solid tumors. 
Concomitant medications, treatment exposure and study drug compliance will be summarized by 
dose cohort for Part 1 and by treatment arm for Part 2.  All summaries will be based on the 
Safety Analysis Set. 
Continuous data will be summarized using the number of patients (n), mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum.  Categorical data will be summarized 
using frequency tabulations (number and percentage of patients). 
Unless specified, no formal statistical hypothesis testing will be conducted and all analyses will 
be descriptive.  Two-sided 95% confidence intervals (CIs) will be presented alongside all point 
estimates to access precision. 
Baseline will be defined as the last measurement obtained prior to the first administration of 
NOX66. 
All statistical analysis will be performed using Statistical Analysis Software (SAS®) Version 9.3 
or higher. 
9.4.2 
Participant Disposition 
The disposition of all patients who sign an ICF will be provided.  The number of patients 
screened, enrolled, who received study drug, completed and discontinued will be summarized as 
well as the reason(s) for screening failure and all post-enrollment study or study drug 
discontinuations. 
9.4.3 
Participant Demographics and Baseline Characteristics 
Participant demographics and baseline characteristics will be summarized separately for each 
study part using appropriate descriptive statistics.  Demographics and baseline characteristics 


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will be summarized for Part 1 by dose cohort and will be based on the Full Analysis Set (FAS).  
For Part 2, demographics and baseline characteristics will be summarized by treatment arm and 
will be based on the FAS. 
Relevant medical history will be summarized in the same manner as described above. 
9.4.4 
Concomitant Medications 
Concomitant medications will be summarized separately for each study part.  All concomitant 
medications will be recorded in the eCRF and will be coded based on World Health Organization 
drug dictionary latest version.  Descriptive summaries will be provided by coded term. 
9.4.5 
Treatment Exposure and Study Drug Compliance 
Extent of exposure to NOX66 will include the following variables: 
• 
Total treatment duration (in weeks) = (date of last treatment – date of first treatment + 1)/7. 
• 
Relative Dose Intensity = 100 * (number of suppositories received/planned number of 
suppositories for duration of treatment). 
A record of the number of NOX66 suppositories dispensed to and taken by each patient will be 
documented.  The proportion of suppositories taken will be calculated and patients will be 
deemed compliant if this proportion is ≥ 80%. 
For EBRT, the date and time of each dose administered will be listed.  The site coordinator will 
confirm this information with the radiologist administering the EBRT and the date of 
administration will be added to the electronic data capture (EDC) system. 
9.4.6 
Primary Endpoint(s) 
9.4.6.1 
Part 1 (Dose Escalation): Recommended Phase 2 Dose 
The primary endpoint for Part 1 (dose escalation) is the number of DLTs, which will be used to 
estimate the MTD and select the RP2D.  This will be determined by the dose level at which no 
more than 1 patient out of 6 patients experiences a DLT during Cycle 1. 
For assessment of DLTs, toxicities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) v22.0 or higher and graded according to NCI-CTCAE v5.0.  See 
Section 7.1.2.2 for details on DLT criteria. 


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The number of DLTs experienced by a patient will be summarized by DLT type for each dose 
cohort and DLT events will be listed by patient.  The listing will include the description, severity 
and relationship of the events to study drug. 
9.4.6.2 
Part 2 (Dose Expansion) 
The primary endpoints for Part 2 (dose expansion) are: 
• 
Arm 1 (mCRPC): The proportion of patients who achieve ≥ 30% reduction in PSA from 
baseline at the end of Cycles 3 and 6. 
• 
Arm 2 (BC and NSCLC): Disease control rate assessed by determining the percentage of 
patients with CR, PR, plus SD. 
For patients with mCRPC, plasma levels of PSA will be collected on Day 1 of Cycles 1 to 5, 
every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at the 6-, 9- and 
12 month Follow-up Visits for all patients including those that discontinued for any reason other 
than disease progression.  The number and proportions of patients with a ≥ 30% reduction in 
PSA levels from baseline to the end of Cycles 3 and 6 (primary endpoint) and change from 
baseline at any time point (secondary endpoint) will be presented for Treatment Arm 1 along 
with the corresponding exact 95% CI (Clopper-Pearson). 
The effect of NOX66 on DCR will be assessed based on the percentage of patients with the best 
overall response of CR or PR at any time plus SD from first dose administration until disease 
progression, death due to any cause or the start of new anticancer therapy, respectively.  
RECIST v1.1 criteria will be applied to assess CR, PR and SD.  Disease control rate will be 
presented for Treatment Arm 2 along with the corresponding exact 95% CI (Clopper-Pearson).  
Tumor imaging and disease response assessments will be performed for up to 12 months after 
the last dose of study drug until disease progression, withdrawal of consent, initiation of new 
anticancer therapy, the patient is lost to follow-up or death, whichever comes first. 
9.4.7 
Secondary Endpoint(s) 
9.4.7.1 
Safety of NOX66 and Both Doses of EBRT 
Safety profiles will be summarized by NOX66 dose cohort and separately by EBRT dose cohort 
(Part 1) or treatment arm and separately by EBRT dose cohort (Part 2) and will be based on the 
Safety Analysis Set. 
Adverse events will be coded using the MedDRA v22.0 or higher and will be graded according 
to the NCI-CTCAE v5.0.  Treatment-emergent AEs are defined as those AEs that either start or 


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worsen in severity on or after the date of first administration of study drug and on or before 
30 days after the last dose of study drug. 
Treatment-emergent AEs will be summarized by severity grade and relationship to study drug.  
Serious AEs, serious TEAEs and TEAEs leading to discontinuation of study drug or to death will 
be presented. 
Changes in clinical laboratory values, vital signs, ECGs and physical examinations will be 
summarized over time. 
9.4.7.2 
Efficacy of NOX66 
The following efficacy analysis will be conducted for the patients enrolled to Part 1 and Part 2 of 
the study.  All analyses are based on the FAS.  Results will be summarized by dose cohort 
(Part 1) or treatment arm (Part 2). 
For patients with mCRPC, the change in PSA from baseline will be summarized by dose cohort 
(Part 1) or treatment arm (Part 2, Arm 1) assessed using samples collected on Day 1 of Cycles 1 
to 5, every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at the 6-, 
9- and 12-month Follow-up visits for all patients including those that discontinued for any reason 
other than disease progression.  A PSA response will be considered as a PSA value reduction ≥ 
30% from baseline at the end of Cycles 3 and 6.  A PSA reduction from baseline at any time 
point will also be assessed as a secondary objective. 
Overall response rate, defined as the percentage of patients with CR and PR, will be assessed 
based on change from baseline imaging (RECIST v1.1 and PCWG-3 criteria for measurable or 
evaluable lesions).  The number and proportion of responders (CR and PR) will be presented 
along with the exact 95% CI (Clopper-Pearson) for the time points after Day 1.  Patients are 
allowed to continue study treatment until disease progression, unacceptable toxicity, withdrawal 
of consent, start of a new anticancer therapy, withdrawal of the patient by the Investigator or 
termination of the study by Sponsor.  Tumor imaging assessment will be continued as scheduled 
for the patients who are discontinued from the study for reasons other than disease progression 
(see Section 8.1.3).  The best overall response (CR, PR, SD or progression) will be summarized. 
The change in ECOG from baseline will be summarized by dose cohort (Part 1) or treatment arm 
(Part 2) over time.  The change in pain severity and pain interference with daily activities from 
baseline will be summarized by dose cohort (Part 1) or treatment arm (Part 2) over time.  The 
number and proportion of patients with a pain response (≥ 2-point reduction in pain severity and 
no additional opioid use) will be summarized over time along with the exact 95% CIs 


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(Clopper-Pearson).  The time to morphine administration and/or use of analgesics together with 
change from baseline assessment will be calculated and summarized by dose cohort (Part 1) and 
treatment arm (Part 2).  The number and proportion of patients with SREs and/or SSEs will be 
summarized at each time point and presented along with the exact 95% CI (Clopper-Pearson). 
Quality of Life analyses will be performed for the Safety Analysis Set.  Scale measures from the 
EORTC-QLQ-C30, BPI-SF, PEQ, and FACT-P (mCRPC patients only) will be summarized for 
all patients by dose at each on-site visit as well as the change from baseline to each on-site visit. 
Survival functions will be computed for OS, PFS and PSA reduction/progression (for Part 2, 
Arm 1 only) using the Kaplan-Meier method.  Estimates of median survival times will be 
presented by dose cohort (Part 1) or treatment arm (Part 2) along with 2-sided 95% CIs.  The 25th 
and 75th percentiles and the range (minimum, maximum) will be presented as well. 
Duration of response is defined as the time from the first documented overall response of CR, PR 
or SD to the first documented overall response of progressive disease.  This will be estimated 
using the Kaplan-Meier method.  Estimates of median survival times will be presented along 
with the two-sided 95% CI.  The 25th and 75th percentiles and range (minimum, maximum) will 
also be presented. 
9.4.7.3 
Pharmacokinetic Evaluation 
Plasma samples will be assayed for idronoxil and up to 7 selected metabolites by validated 
LC-MS/MS.  Individual plasma concentration-time data and plasma PK parameters will be 
summarized using descriptive statistics by treatment day and sampling time for idronoxil and the 
7 detectable metabolites (GIS/SIG, IG, GI, IS, SI, SIS, and GIG).  Plasma PK parameters will be 
determined by noncompartmental analysis for idronoxil and selected metabolites (SI, IS, GI, IG, 
SIG/GIS, GIG, SIS) and will be summarized by dose and treatment day. 
The following PK parameters will be estimated for idronoxil and the selected metabolites 
following the morning dose on Days 1, 6 and 14 of Cycle 1, as data permit: Cmax, Cmin (predose), 
Tmax, AUC(0-t), AUC(0-6), AUC(0-12), AUC(0-inf) and t½.  Details of the analyses will be included in 
the SAP. 
Dose proportionality will be assessed using the power model for Cmax, AUC(0-t), AUC(0-inf), 
AUC(0-6), and AUC(0-12) on Days 1, 6 and 14 of Cycle 1 for the parent compound. 
If data permits, accumulation ratios will be calculated for parent compound and selected 
metabolites for Cmax, Cmin, AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) for Days 6 and 14 of 
Cycle 1 (e.g., Day 14/Day 1 and Day 6/Day 1) and Day 8 of Cycles 2 and 3. 


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The metabolite to parent ratios will be calculated (as data permit) for Days 1, 6 and 14 of 
Cycle 1, for AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) and for single time points on Day 1 of 
Cycles 2 and 3. 
Concentration and PK parameter data will be listed, summarized and plotted.  Details of these 
analyses will be included in the SAP. 
There are no formal PK parameters for concentration data from Cycles 2 and 3 because these are 
single time points.  However, metabolite to parent ratios will be explored. 
Exploratory analyses of the relationship between plasma concentrations of parent drug and 
selected metabolites and/or PK parameters and AEs or PD biomarkers may be assessed by 
graphical methods and special summary tables.  Exposure-response relationship may also be 
explored. 
9.4.7.4 
Pharmacodynamic Biomarker Analysis 
Plasma levels of cytokines and chemokines will be evaluated as part of the PD analysis.  Using 
the plasma samples, analysis will be performed for ctDNA and lipidomic profiling. 
Absolute and change from baseline results of biomarker analysis will be summarized 
descriptively and also presented on a plot. 
9.5 Interim Analyses 
No formal interim analyses are planned. 
9.6 Data Monitoring Committee (DMC) 
A DMC will not be appointed.  Patient safety and scientific integrity of the study will be 
monitored by the SSC. 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 


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o Applicable International Conference for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. 
o Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC. 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, ICH 
GCP guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary.  Patients will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, 
and the IRB/IEC or study center. 


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The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained.  The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient. 
 
Patients who are rescreened are required to sign a new ICF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB 
and signed by all patients subsequently enrolled in the study as well as those currently enrolled in 
the study. 
10.1.4 Data Protection 
Patients will be assigned a unique identifier by the Sponsor.  Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his personal study-related data will be used by the Sponsor in 
accordance with local data protection law.  The level of disclosure must also be explained to the 
patient who will be required to give consent for their data to be used as described in the informed 
consent. 
The patient must be informed that his medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members and by inspectors from regulatory authorities. 
10.1.5 Committees Structure 
An SSC will be responsible for reviewing all safety data (see Section 7.1.2.1). 
10.1.6 Dissemination of Clinical Study Data 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocol[s], IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Investigator and members of his/her research team (including the IRB/IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 


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necessary to obtain informed consent from patients who wish to participate in the clinical study 
or to comply with regulatory requirements. 
The anonymity of participating patients must be maintained.  Patients will be specified on study 
documents (except patient identification Code List Log) by their patient number and year of 
birth, not by name.  The year of birth data will also be available to external study team members 
(e.g., collected on eCRF, central laboratory sample tubes and laboratory documents).  
Documents that identify the patient (e.g., the signed ICF) must be maintained in confidence by 
the Investigator. 
The clinical study may be considered for publication in the scientific literature irrespective of 
whether the results of the clinical study are positive or negative (Section 10.1.10).  In addition, 
the results of clinical studies will be provided on the publicly funded website 
www.ClinicalTrials.gov in line with the applicable regulations. 
10.1.7 Data Quality Assurance 
• 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data).  The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategies (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote or on-site monitoring) are provided in the Monitoring 
Plan. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
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• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP and all applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator after study completion following local regulations or institutional 
policies.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party without 
written notification to the Sponsor. 
• 
All data generated by the site personnel will be captured electronically at each study center 
using eCRFs.  Data from external sources (such as laboratory data) will be imported into the 
database.  Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail.  The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
• 
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application.  The appropriate staff at the study site will answer queries sent 
to the Investigator.  The name of the staff member responding to the query and time and date 
stamp will be captured to provide an audit trail.  Once all source data verification is complete 
and all queries are closed, the monitor will freeze the eCRF page. 
• 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual.  In addition, site personnel 
will receive training on the EDC system/eCRF. 
10.1.7.1 Quality Assurance and Control 
The Sponsor is implementing and maintaining quality assurance (QA) and quality control (QC) 
systems with written SOPs to ensure that studies are conducted, and data are generated, 
documented, recorded and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s).  Where applicable, the QA and QC systems and written SOPs of the 
CRO will be applied. 
The Sponsor or Sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities.  The audit may include on-site review of regulatory documents, eCRFs and source 
documents.  Direct access to these documents will be required by the auditors. 


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10.1.8 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the Investigator’s site. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
Investigator may need to request previous medical records or transfer records, depending on the 
study.  Also, current medical records must be available. 
10.1.9 Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Sponsor may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of patients by the Investigator. 
• 
Discontinuation of further study drug development. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 


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10.1.10 Publication Policy 
• 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor at least 
30 days before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
• 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.  In this 
case, a coordinating Investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.11 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements.  The 
Sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  In addition, for the US, following above 
mentioned approval, the protocol amendment(s) will be submitted to the investigational new 
drug (IND) under which the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment.  All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.12 Liability and Insurance 
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements.  The insurance will cover any injury related to the study drug 
and clinical study experienced by the patient (if the patient followed all protocol procedures and 
restrictions).  The name and address of the relevant insurance company, the certificate of 
insurance, the policy number and the sum insured are provided in the Investigator’s Site File. 
Details are provided in the ICF. 


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10.1.12.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC/eCRF entries and individual patient’s medical records, assess study drug accountability and 
ensure that the study is being conducted according to pertinent regulatory requirements.  
EDC/eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. 
Checking of the EDC/eCRF entries for completeness and clarity and cross-checking with source 
documents, will be required to monitor the progress of the study.  Moreover, regulatory 
authorities of certain countries, IRBs, IECs and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections.  Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality.  The Investigator assures 
Parexel and the Sponsor of the necessary support at all times. 


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10.2 Appendix 2: Clinical Safety Laboratory Tests 
The tests detailed in Table 10-1 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Sections 5.1 
and 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 10-1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
BUN/Urea 
Creatinine 
Glucose (fasting or 
non-fasting) 
CO2/Bicarbonate 
Uric acid 
Potassium 
Sodium 
Calcium 
Chloride 
Magnesium 
Phosphate/ 
Phosphorus 
AST 
ALT 
ALP 
LDH 
GGT 
Total and direct 
bilirubin 
Albumin 
Total cholesterol 
Triglycerides 
 
 
Coagulation 
Prothrombin time, INR, aPTT 
Routine 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, urobilinogen, 
bilirubin, nitrite, WBCs, blood, creatinine (by dipstick) 
Microscopic examination (if blood or protein is abnormal) 
Serology 
HIV, HBsAg, anti-HBc and HCV antibody 
Baseline/Ongoing 
medical 
castration 
(mCRPC patients 
only) 
Testosterone levels 
COVID-19 
Testing (optional) 
SARS-CoV-2 RT-PCR2 


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Laboratory 
Assessments 
Parameters 
Pregnancy 
Testing 
Highly sensitive serum (Screening) and urine (other time points) human 
chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential)3 
NOTES: 
1 All events of ALT  3 × upper limit of normal (ULN) and bilirubin  2 × ULN (> 35% direct bilirubin) or ALT 
 3 × ULN and international normalized ratio (INR) > 1.5, if INR measured which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 To be assessed at Screening, each admission and may optionally be done at additional time points at the 
discretion of the Investigator. 
3 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; anti-HBc = hepatitis B core antibody; 
aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CO2 = carbon dioxide; GGT = gamma glutamyl transferase; HBsAg = hepatitis B surface antigen; HCV = hepatitis 
C virus; HIV = human immunodeficiency virus; IEC = Independent Ethics Committee; INR = international 
normalized ratio; IRB = Institutional Review Board; LDH = lactate dehydrogenase; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; RT-PCR = reverse transcription polymerase 
chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory coronavirus 2; ULN = upper 
limit of normal; WBC = white blood cell 
 
 


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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of a study drug, whether or not considered related to the 
study drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study drug. 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgement of the Investigator (e.g., not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study. 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses 
should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments.  
However, the signs, symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. 


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Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 
was at risk of death at the time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
intervention that would not have been appropriate in the physician’s office or outpatient 
setting.  Complications that occur during hospitalization are AE.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
• Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
• 
Medical or scientific judgement should be exercised in deciding whether SAE 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 medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive intervention 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. 


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10.3.3 Recording and Follow-up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) related to 
the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records 
to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor.  In this case, all patient identifiers, with the exception of the patient number, 
will be redacted on the copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study and classify it into one of Grade 1 through 5 using the NCI-CTCAE v5.0: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications and not bedridden. 


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An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as Grade 3 or higher. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgement to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy and other risk 
factors, as well as the temporal relationship of the event to study drug administration will 
be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor.  However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological examinations or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 


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• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAE  
For studies in the US: 
The Investigator must report any SAEs in the eCRF/EDC system within 24 hours of becoming 
aware of the event.  In the event the EDC system is down, the Investigator must complete the 
SAE form and provide the completed form to the Parexel Clinical Studies Safety Center using 
the email address provided to the sites on the eCRF/SAE form. 
When sending the completed SAE form via email, state that you are reporting an SAE and give 
the Investigator’s name, your name, the telephone number where you can be reached and the 
protocol number and title.  The event must be documented in the eCRF/EDC system when it is 
back online. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/Parexel will evaluate the seriousness and the causal relationship of the event to 
study drug.  In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the reference document (IB or Summary of Product Characteristics).  
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made 
concerning the need for further action. 
All SAEs will be recorded from signing of informed consent until 30 days after the last dose of 
study drug.  Serious adverse events occurring after the end of the study and coming to the 
attention of the Investigator must be reported only if they are considered (in the opinion of the 
Investigator) causally-related to study drug. 


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SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
Parexel International Corporation 
Clinical Studies Safety Center 
Medical Monitor 
Drug Safety Specialist 
(See SAE Reporting Instructions) 
 
1. Telephone the Medical Monitor using the number provided to sites to inform him/her 
that you have completed the SAE eCRF page/SAE form.  If the Medical Monitor is not 
available or you are calling after business hours (8:30 am to 5:30 pm Eastern time, 
Monday to Friday), leave a message in his/her voice mailbox. 
2. Provide the Medical Monitor with the Principal Investigator’s name, your name, the 
telephone number where you can be reached and the protocol number and title. 
3. Inform the Medical Monitor within 24 hours of becoming aware of the event and 
provide any supporting documentation to him/her within this time frame. 
4. After business hours, the Medical Monitor may be reached through Parexel’s 24-hour 
answering service on the number provided to the sites.  Give the answering service the 
protocol number, the study drug name and the Sponsoring pharmaceutical company. 
 
For Studies in the EU: 
All SAEs that occur during the study and all SAEs occurring up to 30 days after receiving the 
last dose of study drug, whether considered to be associated with the study drug or not, must be 
reported within 24 hours in the eCRF/EDC system.  If the EDC system is offline for any reason, 
the Investigator should complete the SAE form and provide the completed form to the Parexel 
Safety Contact using the email address provided to the sites. 
SAEs occurring after the end of the study should be reported to the Sponsor/Parexel by the 
Investigator if the Investigator considers there is a causal relationship with the study drug. 
The minimum information required for an initial report is (in situations where the EDC system is 
offline at time of reporting): 
• 
Name of person sending the report (e.g., name, address of Investigator). 
• 
Patient identification (Screening/participant number, initials, NOT patient name). 
• 
Protocol number. 


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• 
Description of SAE. 
• 
Causality assessment, if possible. 
However, as far as possible all points on the SAE form should be covered in the initial report or 
the completed SAE form itself must be emailed to the Parexel Safety Contact using the 
information provided to study sites.  The original SAE form must then be sent by mail to the 
Parexel Safety Contact.  In addition, the event must be documented in the eCRF/EDC system 
when it is back online. 
In case the Parexel Safety Contact cannot be contacted (e.g., out of normal working hours or at 
weekends), an automated reporting service is available.  The required information should be 
emailed, and a message should be left on the voicemail service (the relevant phone number/email 
address will be provided to all sites). 
After receipt of the initial report, the safety center will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event.  Parexel will 
be responsible for all information processing and reporting according to local legal requirements.  
Where necessary, Investigators will inform regulatory authorities in their own countries. 
For Studies in Australia: 
The Investigator must report any SAEs in the eCRF/EDC system within 24 hours of becoming 
aware of the event.  In the event the EDC system is down, the Investigator must complete the 
SAE form and provide the completed form to the Parexel Clinical Studies Safety Center using 
the email address provided to the sites on the eCRF/SAE form.  The original SAE form must be 
sent by mail to the Parexel Safety Contact and the event must be documented in the eCRF/EDC 
system when it is back online. 
All SAEs will be recorded from signing of informed consent until 30 days after the last dose of 
study drug.  Serious adverse events occurring after the end of the study should be reported to the 
Sponsor/Parexel by the Investigator if the Investigator considers there is a causal relationship 
with the study drug. 
The minimum information required for reporting of an SAE is (in situations where the EDC 
system is offline at the time of reporting): 
• 
Contact details of the person sending the report (e.g., name, address, phone number). 
• 
Patient identifier (e.g., Screening/participant number, initials, date of birth, but not their full 
name). 


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• 
Details of the product involved. 
• 
Protocol number. 
• 
Details of the suspected SAE (including causality and severity assessment). 
In case the Parexel Safety Contact cannot be contacted (e.g., out of normal working hours or at 
weekends), an automated reporting service is available.  The required information should be 
emailed, and a message should be left on the voicemail service (the relevant phone number/email 
address will be provided to all sites). 
After receipt of the initial report, the safety center/Sponsor will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event.  
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made 
concerning the need for further action.  Parexel will be responsible for all information processing 
and reporting according to local legal requirements.  Where necessary, Investigators will inform 
regulatory authorities in their own countries. 


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10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose administration, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
NOTE: Documentation can come from the site personnel’s review of the patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
o A high follicle-stimulating hormone (FSH) level in the post-menopausal range may 
be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  However, in the absence of 
12 months of amenorrhea, a single FSH measurement (> 40 IU/L) is required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 


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Contraception Guidance 
Male Patients: 
Male patients who have had a vasectomy may participate in this study provided that the absence 
of sperm has been confirmed.  If not, an additional highly effective method of contraception 
should be used.  Male patients with female partners of childbearing potential are eligible to 
participate if the agree to ONE of the following during the protocol-defined time frame in 
Section 5.1: 
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent. 
• 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
< 1% per year as described in the table below when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition, male patients must refrain from donating sperm for the duration of the study and for 
3 months after the last dose of study drug. 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female Patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below, and 
to not donate ova, for 3 months after the last dose of study drug. 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of < 1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 


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Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of < 1% per year when used consistently and correctly. 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation2 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If 
not, an additional highly effective method of contraception should be used. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for patients participating in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method.  In this case, two highly effective methods of contraception should be utilized during 
the treatment period and for at least 6 months after the last dose of study drug. 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
• 
Pregnancy testing will be performed according to the standard procedures of the study site. 
• 
Additional pregnancy testing should be performed during the treatment period (at the 
discretion of the Investigator).  During the Follow-up Visit period (up to 3 months after last 
dose of study drug), patients will be questioned about their pregnancy status and use of 
contraception. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 


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Collection of Pregnancy Information: 
Male Patients with Partners Who Become Pregnant 
• 
The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study.  This applies only to 
male patients who receive NOX66. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  The female 
partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to the Sponsor.  Generally, the follow-up 
will be no longer than 3 months following the estimated delivery date.  Any termination of 
the pregnancy will be reported regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
Female Patients Who Become Pregnant 
• 
The Investigator will collect pregnancy information on any female patients who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient’s pregnancy.  The 
patient will be followed to determine the outcome of the pregnancy.  The Investigator will 
collect any follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor.  Generally, follow-up will not be required for longer than 3 months 
beyond the estimated delivery date.  Any termination of the pregnancy will be reported, 
regardless of fetal state (presence or absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such.  Any post-study 
pregnancy-related SAE considered reasonably related to study drug by the Investigator will 
be reported to the Sponsor as described in Section 8.3.4.  While the Investigator is not 
obligated to actively seek this information in former study patients, he or she may learn of an 
SAE through spontaneous reporting. 
• 
Any female patient who becomes pregnant while participating in the study will discontinue 
study drug or will be withdrawn from the study. 
 
 


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10.5 Appendix 5: Tumor Imaging 
The revised RECIST guideline (version 1.1) will be used for assessment of tumor response in 
soft tissue lesions.  While either CT or MRI may be utilized, as per RECIST v1.1, CT is the 
preferred imaging technique in this study.6 
Bone lesions (mCRPC patients only) will be assessed using PCWG-37 criteria. 
 
 


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10.6 Appendix 6: European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire for Cancer Patients 
(EORTC-QLQ-C30) 
 


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10.7 Appendix 7: Brief Pain Inventory – Short Form 
 


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10.9 Appendix 9: Functional Assessment of Cancer Therapy – Prostate 
(FACT-P) Version 4 
 


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10.10 Appendix 10: Guidance for Low-Dose EBRT 
Simulation and Motion Management 
Simulation study using either CT or MRI +/- PET scans should be carried out as part of 
treatment planning.  The imaging will be performed to acquire the anatomy involved in the 
treatment with at least 5 cm of additional margin outside the planned radiation field to allow for 
adequate dose calculations.  The simulation scan will be used to identify the lesion(s) and 
surrounding normal critical organs to develop a treatment plan to deliver radiation in a manner 
that targets the lesion(s) accurately and spares critical organs as much as possible.  The 
simulation needs to account for tumor mobility and the scan techniques, where applicable, need 
to account for respiration, cardiac function, peristaltic activity, and organ filling and emptying. 
The utilization of 4D simulation technique will be at the treating physician discretion when 
treating 8 Gy in 1 fraction or 20 Gy in 4 fractions.  When treating with 25 Gy in 5 fractions, 4D 
simulation technique will be required in non-spinous lesions within 10 cm (either inferior or 
superior) of the diaphragm.  When 4D simulation technique is utilized multiple images will be 
acquired and regular points along the patients breathing cycle utilizing equipment and practices 
detailed by treatment site SOPs.  An internal gross tumor volume (iGTV) will be contoured to 
encompass the full range of tumor motion to be utilized for treatment planning purposes.  It will 
be up to the treating physician’s discretion to use techniques to reduce tumor motion and 
facilitate tumor tracking.  These techniques include breath-hold, abdominal compression, and 
fiducial marker placement.  
Guidelines described here will be superseded by any site-specific SOPs that require a higher 
degree of stringency. 
Immobilization 
Any immobilization equipment used must be fit for purpose.  When immobilizing the patient in 
preparation for treatment, it is necessary to ensure the patient is as comfortable as possible and is 
in a stable position.  This position needs to be reproducible at the time of treatment. 
Immobilization techniques must take into account the individual patient needs, organ motion and 
the complexity of the proposed radiation therapy technique.  Given treatment center variations in 
immobilization techniques, treatment-site SOPs will be followed regarding specific device 
utilization.  These devices include customized devices such as thermoplastic masks and 
vacuum-assisted immobilization devices (e.g., Vac-Lok), placement of radiopaque markers and 
marking tattoos, and non-custom devices such as wing board and MedTec devices. 


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Comprehensive documentation that itemizes patient immobilization methods and set-up details is 
required to ensure that the optimal treatment position is achieved and reproducibility errors are 
minimized. 
Treatment Planning and Verification 
• 
Dose prescribed will be 8 Gy in 1 fraction or 20/25 Gy in 5 fractions, aiming to cover at least 
99% of the PTV by 95% of the prescribed dose 
• 
No ‘hotspots’ within or outside of the PTV to exceed 110% of prescribed dose 
Treatment planning will include imaging procedures that will localize, delineate, and define 
target volumes and organs at risk, as well as enabling treatment verification.  This should be 
done according to the institutional SOP and allow both forward and inverse planning techniques 
where appropriate. 
Treatment planning needs to include: 
• 
Positioning and immobilization 
• 
Use of optimal imaging modalities 
• 
Delineation of treatment fields and isocenters 
• 
Measurements and patient contouring 
• 
Documentation 
• 
Patient consent to perform permanent skin marking procedures 
Treatment verification needs to match the simulated/planned treatment parameter with that set on 
the treatment unit.  The position of the treatment isocenters, radiation treatment field and/or its 
shape or anatomical volume must be evaluated against that determined in the treatment planning 
process. 
The EBRT to be administered in the context of this study is for symptomatic relief and pain 
management, and not for the purpose of ablative therapy.  As such, the prescribed EBRT should 
only be given to target lesions and normal tissues should be spared.  If 25 Gy in 5 fractions is 
prescribed, it will be encouraged but not required that daily kV or MV imaging is obtained with 
every fraction and that on-board axial imaging is obtained on the first day of treatment. 
For 25 Gy in 5 fractions, images must be obtained for image guidance prior to each fraction to 
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Normal Tissue Constraints  
In the context of this study, it is a requirement that the radiation oncologist will follow the 
QUANTEC Guidelines for normal tissue constraints when administering low-dose EBRT (20 Gy 
in 5 fractions or 8 Gy in 1 fraction) to metastatic lesions7.  For 25 Gy in 5 fractions, the dosing 
guidance from the AAPM Task Force Group 101 has to be followed2.  This study will be 
excluding all patients who have central nervous system involvement; therefore, the CNS tissue 
tolerances, with the exception of spinal cord exposure, will not be included in the guidance on 
normal tissue dose constraints as set out below.  These constraints are for EBRT at low dose and 
for standard fractionation. 
Tissue / Organ 
Tissue radiation dose constraints 
(maximum radiation dose) 
Spinal cord 
23 Gy 
Retina 
< 50 Gy 
Cochlea 
≤ 45 Gy 
Single parotid gland sparing 
< 20 Gy 
Irradiation to 2 parotid glands 
< 25 Gy (spread across 2 glands) 
Mandible 
≤ 70 Gy 
Pharyngeal constrictors 
< 50 Gy 
Larynx 
< 44 Gy 
Brachial plexus 
< 60 Gy 
Lung 
20 Gy 
Oesophagus 
< 34 Gy 
Heart 
< 26 Gy 
Liver 
≤ 28 Gy 
Kidney 
< 18 Gy per kidney 
Stomach 
< 50Gy 
Small bowel (irradiation to less than one-
third) 
50 Gy 
Rectum 
< 27 Gy 
Skin 
40 Gy 
Bladder 
< 65 Gy 
Femoral head 
< 52 Gy 
 


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Equipment 
Radiation delivery equipment needs to have undergone appropriate dosimetry calibration using 
an acceptable phantom to ensure that the correct treatment beam energies are being generated, 
correct alignment between on-board imaging and treatment isocenter, and accurate motion of the 
treatment couch.  This calibration needs to be performed at a minimum of once every 3-4 years 
to ensure acceptable quality control as per treatment site SOPs. 
Treatment Dose Interruptions 
Treatment dose interruption for the single fraction Gy regimen is not applicable. 
For a patient who will be receiving 20/25 Gy over 5 fractions, dose interruption must occur if a 
patient experiences a Grade 3 or higher adverse reaction in any organ/tissue that is due to the 
radiation therapy.  The fractionated therapy can only resume once the adverse reaction has 
recovered or stabilized back to Grade 2 or less. 
Patients with tumors involving the central nervous system are excluded from this study.  It is 
anticipated that over 50% of patients recruited into this study will require symptomatic low-dose 
EBRT to bony metastases, with involvement of other soft tissue organ lesions for the rest of the 
patients. 
References 
1. Radiation Oncology Practice Standards Part B: Guidelines.  The Royal Australian and 
New Zealand College of Radiologists – Faculty of Radiation Oncologists. 
2. Benedict SH et al.  Stereotactic body radiation therapy: The report of the AAPM Task 
Group 101.  Med Phys.  37(3): August 2010. 
3. RTOG/EORTC Late Radiation Morbidity Scoring System.  http://wwwrtog.org/Research 
Associates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchem
a.aspx 
4. de Ruysscher D et al.  European Organisation for Research and Treatment of Cancer 
(EORTC) recommendations for planning and delivery of high-dose, high precision 
radiotherapy for lung cancer.  Radiotherapy and Oncology.  124 (2017): 1-10. 
5. Boehmer D et al.  Guidelines for primary radiotherapy of patients with prostate cancer. 
Radiotherapy and Oncology.  79 (2006): 259-269. 
6. Emami B. Tolerance of Normal tissue to Therapeutic Radiation.  Reports of Radiotherapy 
and Oncology. Vol. 1No. 1. Spring 2013. 


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7. Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). Int. J. 
Radiation Oncology Biol. Phys., Vol. 76, No. 3 Supplement, pp. S1-S160. 2010 


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10.11 Appendix 11: Country-Specific Requirements 
<To be adjusted per country requirements> 
 
 


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10.12 Appendix 12: Abbreviations and Trademarks 
ADL 
Activities of daily life 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
Akt 
Antiapoptotic kinase B 
ALT 
Alanine aminotransferase 
Anti-HBc 
Hepatitis B core antibody 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC(0-6) 
AUC from time zero (predose) to 6 hours postdose 
AUC(0-12) 
AUC from time zero (predose) to 12 hours postdose 
AUC(0-inf) 
AUC from time zero (predose) extrapolated to infinity 
AUC(0-t) 
AUC from time zero (predose) to time of last quantifiable concentration 
BC 
Breast cancer 
BID 
Twice daily 
BP 
Blood pressure 
BPI-SF 
Brief Pain Inventory – Short Form 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
COVID-19 
Coronavirus disease 2019 
CO2 
Carbon dioxide 
CR 
Complete response 
CRO 
Clinical Research Organization 
CT 
Computerized tomography 
ctDNA 
Circulatory tumor deoxyribonucleic acid 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
EBRT 
External beam radiotherapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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eCRF 
Electronic case report form 
ED 
Early Discontinuation 
EDC 
Electronic data capture 
ENOX 
Ecto-NOX disulfide-thiol exchanger 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire for Cancer Patients 
EOT 
End of Treatment 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
Gy 
Gray 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LuPSMA-617 
177lutetium prostate-specific membrane antigen 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
n 
Number of patients/events 


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NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NCSLC 
Non-small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PCWG-3 
Prostate Cancer Working Group 3 
PD 
Pharmacodynamic(s) 
PEQ 
Patient Experience Questionnaire 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PI3 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic(s) 
PPS 
Per protocol Set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PSA 
Prostate-specific antigen 
PSMA 
Prostate-specific membrane antigen 
QA 
Quality assurance 
QC 
Quality control 
QoL 
Quality of life 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
RT-PCR 
Reverse transcription polymerase chain reaction 
S1P 
Sphingosine-1-phosphate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis Software 
SD 
Stable disease 
SoA 
Schedule of Activities 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SRE 
Skeletal-related events 


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SSC 
Safety Steering Committee 
SSE 
Symptomatic skeletal events 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal phase half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to first occurrence of Cmax 
TMEP 
Transmembrane electron potential 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
 
 
 


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11 References 
1. Crumbaker M, Pathmanandavel S, Yam AO, Nguyen A, Ho B, Chan L, et al.  Phase I/II 
Trials of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and 
Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer 
(LuPIN).  European Association of Urology 2020 (accessed 17 Sep 2020).  Available online 
at: https://doi.org/10.1016/j.euo.2020.07.002. 
2. Investigator’s Brochure – NOX66.  Noxopharm Limited.  Edition 8.0, 11 Feb 2021. 
3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.  Global Cancer Statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 
185 countries.  CA Cancer J Clin. 2018;68(6):394-424. 
4. Pathmanandavel S, Crumbaker M, On Wah Yam A, Rofe C, Ho B, Ling Chan W, et al. Final 
results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of 
combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic 
castration-resistant prostate cancer (LuPIN trial). [Poster] Exhibited at: 2021 Genitourinary 
Cancers Symposium. Available at: https://meetinglibrary.asco.org/record/194976/abstract 
5. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP.  
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group.  Am J Clin 
Oncol. 1982;5(6):649-655. 
6. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation criteria 
in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
7. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the 
Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. 
 
 


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Investigator Agreement Page 
Declaration of the Principal or Global Coordinating Investigator 
<This page should be used for studies with EU sites but is not mandatory for US studies.> 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
This study protocol (Version 3.0, dated 21 Jan 2022) was subjected to critical review and has 
been approved by the Sponsor.  The information it contains is consistent with the current 
risk/benefit evaluation of the study drug as well as with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki, as amended in 
1996 and the guidelines on Good Clinical Practice. 
Principal or Global Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 


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Declaration of the National Coordinating Investigator <country-specific, please adjust as 
required> 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
This study protocol (Version 3.0, dated 21 Jan 2022) was subjected to critical review and has 
been approved by the Sponsor.  The information it contains is consistent with the current 
risk/benefit evaluation of the study drug as well as with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki, as amended in 
1996 and the guidelines on Good Clinical Practice. 
National Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 


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Declaration of the Investigator 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol (Version 3.0, dated 21 Jan 2022), Investigator's Brochure, EDC system/electronic CRF 
(eCRF) and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC.  No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 

Prot_SAP_000.pdf: 
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Title Page 
Protocol Title: 
A Phase 1b/2a Multicenter Study of NOX66 and 
External Beam Radiotherapy in Patients with 
Metastatic Castration-resistant Prostate Cancer and 
Other Solid Tumors 
Compound: 
NOX66 (active ingredient: Idronoxil) 
Trade Name: 
Not applicable 
Indication: 
Metastatic castration-resistant prostate cancer and 
other solid tumors 
Study Sponsor: 
Noxopharm Limited 
Level 20, Tower A, The Zenith 821 Pacific 
Highway, Chatswood NSW 
Australia 
Sponsor Protocol Number: 
NOX66-005 
Development Phase: 
Phase 1b/Phase 2a 
Regulatory Agency Identifying 
Number: 
154874 
Approval Date: 
Final 4.0, 23 Nov 2022  
 
 


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Sponsor Signatory: 
 
 
 
 
Dr Gisela Mautner 
Chief Medical Officer 
 
Date 
 
Medical Monitor Name and Contact Information will be provided separately. 
 
 


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Table of Contents 
 
Table of Contents ............................................................................................................................ 3 
1 
Protocol Summary .................................................................................................................... 8 
1.1 
Synopsis ................................................................................................................................ 8 
1.2 
Schema ............................................................................................................................... 27 
1.3 
Schedule of Activities ......................................................................................................... 31 
1.3.1 
Electrocardiogram Schedule ........................................................................................... 41 
1.3.2 
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1 and Part 2 ...... 42 
2 
Introduction............................................................................................................................. 44 
2.1 
Study Rationale .................................................................................................................. 44 
2.2 
Background......................................................................................................................... 45 
2.3 
Benefit/Risk Assessment .................................................................................................... 47 
2.3.1 
Risk Assessment ............................................................................................................. 47 
2.3.2 
Benefit Assessment ......................................................................................................... 49 
2.3.3 
Overall Benefit: Risk Conclusion ................................................................................... 50 
3 
Objectives and Endpoints ....................................................................................................... 50 
4 
Study Design ........................................................................................................................... 52 
4.1 
Overall Design .................................................................................................................... 52 
4.1.1 
Part 1 (Dose Escalation) ................................................................................................. 55 
4.1.2 
Part 2 (Dose Expansion) ................................................................................................. 57 
4.2 
Scientific Rationale for Study Design ................................................................................ 57 
4.3 
Justification for Dose .......................................................................................................... 59 
4.4 
End of Study Definition...................................................................................................... 59 
5 
Study Population ..................................................................................................................... 59 
5.1 
Inclusion Criteria ................................................................................................................ 60 
5.2 
Exclusion Criteria ............................................................................................................... 62 
5.3 
Screen Failures ................................................................................................................... 65 
5.3.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 65 
6 
Study Drug .............................................................................................................................. 65 
6.1 
Study Drug(s) Administered ............................................................................................... 65 
6.1.1 
Radiotherapy ................................................................................................................... 67 


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6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 68 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 68 
6.4 
Study Drug Compliance ..................................................................................................... 69 
6.5 
Concomitant Therapy ......................................................................................................... 70 
6.6 
Dose Modification .............................................................................................................. 70 
6.6.1 
Dose Modification of Radiotherapy ............................................................................... 72 
6.7 
Study Drug After the End of the Study .............................................................................. 72 
7 
Discontinuation of Study Drug and Participant Discontinuation ........................................... 72 
7.1 
Discontinuation of Study Drug ........................................................................................... 72 
7.1.1 
Safety Stopping Criteria: ................................................................................................ 72 
7.1.2 
Dose Escalation Rules and Safety Steering Committee ................................................. 73 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................... 77 
7.3 
Loss of Participants to Follow-Up ...................................................................................... 78 
8 
Study Assessments and Procedures ........................................................................................ 78 
8.1 
Efficacy Assessments ......................................................................................................... 79 
8.1.1 
Prostate-specific Antigen (PSA) Response and Progression (mCRPC only) ................. 80 
8.1.2 
Disease Control Rate ...................................................................................................... 80 
8.1.3 
Tumor Imaging Assessment ........................................................................................... 80 
8.1.4 
Eastern Cooperative Oncology Group Performance Status Score ................................. 82 
8.1.5 
Clinical Outcome Assessment ........................................................................................ 82 
8.1.6 
Morphine Administration and Analgesic Use ................................................................. 84 
8.1.7 
Skeletal-related Events and Symptomatic Skeletal Events Assessment ......................... 84 
8.1.8 
Progression-free Survival ............................................................................................... 84 
8.1.9 
Overall Survival .............................................................................................................. 84 
8.1.10 
Overall or Objective Response Rate ............................................................................... 84 
8.2 
Safety Assessments ............................................................................................................. 85 
8.2.1 
Administrative Procedures ............................................................................................. 85 
8.2.2 
Screening and Eligibility Assessments ........................................................................... 85 
8.2.3 
Dose-limiting Toxicity .................................................................................................... 87 
8.2.4 
Physical Examinations .................................................................................................... 87 
8.2.5 
Vital Signs ...................................................................................................................... 88 
8.2.6 
Electrocardiograms ......................................................................................................... 88 
8.2.7 
Clinical Safety Laboratory Assessments ........................................................................ 89 
8.2.8 
Radiotherapy Treatment Interruptions ............................................................................ 90 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 90 


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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 90 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 91 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 91 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 91 
8.3.5 
Pregnancy ....................................................................................................................... 92 
8.3.6 
Cardiovascular and Death Events ................................................................................... 92 
8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 93 
8.3.8 
Adverse Events of Special Interest ................................................................................. 93 
8.4 
Treatment of Overdose ....................................................................................................... 93 
8.5 
Pharmacokinetics ................................................................................................................ 93 
8.6 
Pharmacodynamics ............................................................................................................. 94 
8.7 
Genetics .............................................................................................................................. 94 
8.8 
Biomarkers ......................................................................................................................... 94 
8.9 
Archival and Fresh Tissue Biopsy ...................................................................................... 95 
8.10 Immunogenicity Assessments ............................................................................................ 95 
8.11 Health Economics or Medical Resource Utilization and Health Economics ..................... 95 
9 
Statistical Considerations........................................................................................................ 95 
9.1 
Statistical Hypotheses ......................................................................................................... 95 
9.2 
Sample Size Determination ................................................................................................ 96 
9.3 
Populations for Analyses .................................................................................................... 96 
9.4 
Statistical Analyses ............................................................................................................. 97 
9.4.1 
General Considerations .................................................................................................. 97 
9.4.2 
Participant Disposition ................................................................................................... 97 
9.4.3 
Participant Demographics and Baseline Characteristics ................................................ 98 
9.4.4 
Concomitant Medications ............................................................................................... 98 
9.4.5 
Treatment Exposure and Study Drug Compliance ......................................................... 98 
9.4.6 
Primary Endpoint(s) ....................................................................................................... 98 
9.4.7 
Secondary Endpoint(s) ................................................................................................... 99 
9.5 
Interim Analyses ............................................................................................................... 102 
9.6 
Data Monitoring Committee (DMC) ................................................................................ 102 
10 Supporting Documentation and Operational Considerations ............................................... 103 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .......................... 103 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 103 
10.1.2 
Financial Disclosure ..................................................................................................... 103 


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10.1.3 
Informed Consent Process ............................................................................................ 104 
10.1.4 
Data Protection ............................................................................................................. 104 
10.1.5 
Committees Structure ................................................................................................... 105 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 105 
10.1.7 
Data Quality Assurance ................................................................................................ 105 
10.1.8 
Source Documents ........................................................................................................ 107 
10.1.9 
Study and Site Start and Closure .................................................................................. 107 
10.1.10 Publication Policy ......................................................................................................... 108 
10.1.11 Protocol Approval and Amendment ............................................................................. 108 
10.1.12 Liability and Insurance ................................................................................................. 108 
10.2 Appendix 2: Clinical Safety Laboratory Tests ..................................................................110 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ..................................................................................................112 
10.3.1 
Definition of AE ............................................................................................................112 
10.3.2 
Definition of SAE ..........................................................................................................113 
10.3.3 
Recording and Follow-up of AE and SAE ....................................................................115 
10.3.4 
Reporting of SAE ..........................................................................................................117 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ............ 121 
10.5 Appendix 5: Tumor Imaging ............................................................................................ 125 
10.6 Appendix 6: European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire for Cancer Patients (EORTC-QLQ-C30) .................................................. 126 
10.7 Appendix 7: Brief Pain Inventory – Short Form .............................................................. 128 
10.8 Appendix 8: Patient Experience Questionnaire (PEQ) .................................................... 130 
10.9 Appendix 9: Functional Assessment of Cancer Therapy – Prostate (FACT-P) Version 4 134 
10.10 Appendix 10: Guidance for Low-Dose EBRT ................................................................. 137 
10.11 Appendix 11: Country-Specific Requirements ................................................................. 142 
10.12 Appendix 12: Abbreviations and Trademarks .................................................................. 143 
11 References............................................................................................................................. 147 
Investigator Agreement Page ...................................................................................................... 148 
List of Figures 
Figure 1–1: 
Study Design: Part 1 ............................................................................................. 27 
Figure 1–2: 
Study Design: Part 2 ............................................................................................. 30 


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List of Tables 
Table 1-1 
Schedule of Activities (SoA) – Part 1 and Part 2 .................................................. 31 
Table 1-2 
Electrocardiogram Schedule: Part 1 (All Patients) and Part 2 (Only for First 10 
Patients in Each Tumor Type) ............................................................................... 41 
Table 1-3 
Pharmacokinetic Sampling Schedule Following Morning Dose – Part 1 (All 
Patients) and Part 2 (Only for First 10 Patients in Each Tumor Type) ................. 42 
Table 1-4 
Pharmacodynamic Sampling Schedule – Part 1 and Part 2 (All Patients) ............ 43 
Table 1-5 
Optional Archival Tissue Collection and Fresh Biopsy Sampling Schedule – 
Part 1 and Part 2 (All Patients) ............................................................................. 43 
Table 3-1 
Objectives and Endpoints ..................................................................................... 50 
Table 4-1 
Proposed Doses for NOX66 (Part 1) .................................................................... 56 
Table 6-1 
Study Drug(s) Administered ................................................................................. 66 
Table 6-2 
Dose Modification of Study Treatment NOX66 ................................................... 71 
Table 6-3 
Management of NOX66 Treatment-related Toxicity ............................................ 71 
Table 8-1 
Eastern Cooperative Oncology Group Performance Status Score ........................ 82 
Table 9-1 
Populations for Analysis ....................................................................................... 96 
Table 10-1 
Protocol-Required Safety Laboratory Assessments .............................................110 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in 
Patients with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
Sponsor Protocol No.: NOX66-005 
Development Phase: Phase 1b/Phase 2a 
Sponsor: Noxopharm Limited 
Study Sites and Locations: Approximately 14 sites in Australia, United States and Europe 
Rationale: 
Idronoxil, which is the active ingredient of the NOX66 formulation, is a synthetic flavonoid 
derivative of genistein that inhibits external Ecto-NOX disulfide-thiol exchanger (ENOX) 2 to 
induce apoptosis.  ENOX2 inhibition activates the sphingomyelinase pathway and deactivates 
the antiapoptotic protein kinase B pathway, a key driver of radiotherapy resistance.  The targeted 
effect on ENOX2 has the potential to limit toxicity to non-cancer cells, which preferentially 
express ENOX1.  Previous studies have demonstrated improved radiation sensitivity in prostate 
cancer with flavonoid derivatives.  Early studies of intravenous and oral formulations of 
idronoxil were hampered by limited bioavailability.  The Sponsor has sought to address the 
problem of extensive drug metabolism through the development of a rectal suppository dosage 
form.  With blood draining from the distal part of the rectum directly into the inferior vena cava, 
first pass liver metabolism can be avoided.  In the case of a diphenolic drug such as idronoxil, the 
bioavailability is augmented by the rectal mucosa being known to be devoid of transferase 
activity and therefore the phase II metabolism is significantly reduced.  These two aspects 
combined are the basis for the rationale that idronoxil delivered via the rectum is subjected to 
less phase I and phase II metabolism than that observed for orally administered idronoxil.  
NOX66 is a suppository dosage form of idronoxil in a proprietary fatty base containing a 
surfactant.  This formulation is novel in that a lipophilic active ingredient is dispersed in a 
lipophilic suppository base – compared with traditional suppository formulations whereby a 
hydrophilic base would normally be utilized.  Moreover, this suppository dosage form provides a 
slow and sustained release of idronoxil comparable to an intravenous infusion. 


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The first clinical study with NOX66 (NOX66-001A) was a Phase 1a/1b study in which NOX66 
was evaluated both as a monotherapy and in combination with carboplatin, in patients with 
refractory solid tumors.  Two breast cancer (BC) patients and one ovarian cancer patient enrolled 
in this study had reductions in target lesions size with one BC patient showing target lesion 
disappearance (as per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1.) at the end 
of the study. 
The NOX66-002A study evaluated NOX66 in combination with external beam radiotherapy 
(EBRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).  Twenty-five 
patients received radiation therapy and 7 to 16 days of NOX66 treatment in this study. 
The overall radiological assessment according to RECIST v1.1 at 3 months for 19 evaluable 
patients resulted in 17 patients with disease control (1 patient in the 800 mg and 2 patients in 
1200 mg dose cohort with partial response [PR], 14 patients with stable disease [SD]) and 
2 patients, 1 each in the 400 mg and 800 mg cohorts, respectively, with disease progression.  At 
6 months and of the 15 evaluable patients, 1 continued to have PR and 60% continued to have 
SD.  There were two changes among the patients with PR in the 1200 mg cohort, with 1 patient 
not evaluable due to withdrawal and the other patient progressing to disease progression by 
RECIST v1.1 criteria while maintaining a prostate-specific antigen (PSA; 69%) and pain 
response (69% in overall pain score). 
The overall disease control rate (DCR) at 6 months was 66.6% (10/15), with 9 patients having 
SD and 1 patient PR.  The patient with PR also had a PSA decrease of 86% and a symptom 
control response of being 100% pain-free.  A clinical meaningful response in a non-irradiated 
lesion was also observed in the same patient, with a reduction in tumor size of 26.1% from 
baseline at 3 months and a continued decline to 49.3% at 6 months (abscopal response).  Four of 
15 patients had an abscopal response in non-irradiated lesions that were outside of the radiation 
field. 
NOX66 is designed to improve drug delivery and exposure of idronoxil to tumor cells.  This 
Phase 1b/Phase 2a clinical study will explore higher doses of NOX66 and expand the experience 
of NOX66 in men with mCRPC and patients with other solid tumors to determine the 
recommended Phase 2 dose (RP2D) and provide preliminary evidence on overall tumor response 
rate, survival, symptomatic relief of pain as well as other symptoms of this disease, and effects 
on PSA levels (for mCRPC patients only). 


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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Objectives and Endpoints 
Part 1 (Dose Escalation): 
The primary objective for Part 1 will be determined 
based on the count of DLTs. 
To determine the MTD and RP2D of 
NOX66 in combination with low-dose 
EBRT in patients with any solid tumor 
• 
MTD is defined as the dose level at which no 
more than 1 patient out of 6 experiences a DLT 
at the end of Cycle 1. 
• 
RP2D is the highest dose administered at which 
no more than 1 patient out of 6 experiences a 
DLT at the end of Cycle 1 and the dosage form, 
including the dosing frequency, is acceptable to 
patients. 
Part 2 (Dose Expansion): 
 
Arm 1: To evaluate the effect of NOX66 
on PSA response in patients with 
mCRPC. 
 
 
• 
PSA response is defined as the proportion of 
patients with a reduction in PSA in plasma 
(ng/mL) of ≥ 30% from baseline at the end of 
Cycles 3 and 6. 
• 
 
Secondary Objectives and Endpoints 
Characterize the safety and tolerability 
of NOX66 
Safety and tolerability of NOX66 as determined by 
AEs, TEAEs, clinical laboratory evaluations, vital 
signs, 12-lead ECG and physical examinations. 
Evaluate the safety and tolerability of 
both doses of EBRT 
Safety and tolerability of both doses of EBRT as 
determined by AEs, TEAEs, clinical laboratory 
evaluations, vital signs, 12-lead ECG and physical 
examinations. 
Evaluate the exposure of idronoxil 
Concentration of idronoxil and selected metabolites 
in plasma and derived PK parameters, including but 
not limited to: Cmax, Tmax, AUC(0-t), AUC(0-6), 
AUC(0-12), AUC(0-inf), Cmin and t½, as data permit. 


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Objectives 
Endpoints 
Evaluate the preliminary clinical 
efficacy of NOX66 plus low-dose 
EBRT in patients with mCRPC and 
other solid tumors 
Preliminary clinical efficacy as determined by: 
• 
Change from baseline in PSA (mCRPC only) at 
any time point. 
• 
Overall response rate assessed by RECIST v1.1 
criteria (all tumor types) and PCWG-3 criteria 
(mCRPC). 
• 
Duration of response (for patients with 
measurable disease). 
• 
Change from baseline ECOG scores. 
• 
Change from baseline in tumor size and number. 
• 
PFS and OS. 
Explore the effects of NOX66 on pain 
and other cancer-related signs and 
symptoms 
Effects on pain and other cancer-related signs and 
symptoms as determined by: 
• 
Change from baseline in pain scores based on 
the BPI-SF questionnaire. 
• 
SREs and SSEs. 
• 
Change of dose and frequency of morphine 
administration and analgesic use. 
Evaluate the QoL using PRO 
questionnaires 
QoL as assessed by: 
• 
Change from baseline in PEQ. 
• 
Change from baseline in EORTC-QLQ-C30. 
• 
Change from baseline in FACT-P (mCRPC 
only). 
Exploratory Objectives and Endpoints 
Characterize the relationship between 
pharmacodynamic biomarkers and 
idronoxil plasma concentrations (if a 
meaningful change is observed) 
• Change in biomarkers (cytokines, chemokines 
and ctDNA) from baseline. 
• Change in lipid profile from baseline. 
Part 2 - Arm 2: Dose expansion cohort 
(BC and NSCLC) 
To evaluate the effect of NOX66 on 
DCR in patients with BC and NSCLC. 
• DCR is measured by the percentage of patients 
with a best overall confirmed response of CR or 
PR and SD. 
AE = adverse event; BC = breast cancer; BPI-SF = Brief Pain Inventory – Short Form; CR = complete response; 
ctDNA = circulatory tumor deoxyribonucleic acid; DCR = disease control rate; DLT = dose-limiting toxicity; 
EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
for Cancer Patients; FACT-P: Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic 
castration-resistant prostate cancer; MTD = maximum tolerated dose; NSCLC = non-small-cell lung cancer; 
OS =  overall survival; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; PRO = Patient Reported 
Outcome; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid 


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Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; SRE = skeletal-related events; 
SSE = symptomatic skeletal events; TEAE = treatment-emergent adverse event 
 
Overall Design: 
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, 
RP2D, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil 
when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) 
and patients with mCRPC, BC and non-small-cell lung cancer (NSCLC) (Part 2) who are eligible 
for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for the 
prevention of symptoms).  The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 
(dose expansion).  The study design allows an exploration of different doses of NOX66 (800 mg, 
1200 mg, 1600 mg and 2400 mg) with safety monitoring to ensure the safety of the patients.  A 
Safety Steering Committee (SSC) will review available safety data after the first cycle (21 days) 
of each dose cohort of NOX66 in Part 1 to determine the maximum tolerated dose (MTD)/RP2D. 
In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day 
cycle.  From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest 
period on a 14-day cycle.  Patients will continue to receive NOX66 on a cyclical basis until 
disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer 
therapy, withdrawal of the patient by the Investigator or the defined end of study is reached.  
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gray (Gy) as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be administered on Day 2 of Cycle 1 and the remaining dose 
fractions will be given between Day 3 and Day 11.  The choice of one of the EBRT 
dose/fractions stated above will be at the discretion of the Investigator and will be determined by 
the clinical requirements of the patient.  EBRT will be administered according to the institutional 
protocol. 
The expected study duration for a patient from the time of Screening will be a minimum of 7 
months, unless the patient develops progressive disease sooner, but may be longer than 7 
months. The duration from Screening and initial administration of NOX66 until the last study 


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visit is determined by the number of treatment cycles each patient receives plus the follow-up 
period, which is from the last dose of NOX66 until disease progression, withdrawal of consent, 
death or the defined end of study, whichever is shorter.  
There will be a Screening period of up to 27 days (Days -28 to -2).  Each patient will attend the 
study center on Day -1 of Cycle 1 for eligibility assessments and on all PK days 
(Cycle 1: Days 1, 2, 6, 14 and 15; Cycles 2 and 3: Days 1 and 8).  Patients in Part 1 may require 
an overnight stay on Day 1 of Cycle 1.  On Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3, the NOX66 morning administration will occur at the study center under medical 
supervision.  During these days blood samples for PK analysis will be collected as per the 
schedule mentioned in Table 1-3.  In addition to PK samples, patients will be monitored for 
cardiac effects using 12-lead electrocardiograms (ECGs) (Table 1-2).  NOX66 will be 
self-administered by the patients or administered by their care giver at home on all other dosing 
days as well as the evening doses of NOX66 on PK days (Cycle 1: Days 2, 6 and 14; Cycles 2 
and 3: Day 1).  The evening dose of Day 1 of Cycle 1 (in Part 1 only) will be administered at the 
clinical unit.  Patients or care givers should always wear gloves when handling and/or during 
administration of NOX66.  The use of a small amount of water-soluble lubricant is advised 
before rectal administration.  Further administration and handling instructions are provided in the 
“Instructions for Administration of NOX66 Suppositories” document.  Patients will also attend 
the study center for EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively) on 
Days 2 to 11 of Cycle 1 depending on the number of fractions administered.  From Cycle 2 
onwards only NOX66 will be administered for 7 days followed by a 7-day rest period (as 
indicated above).  Patients with mCRPC may also receive androgen deprivation therapy as 
maintenance therapy and patients with BC may receive background hormonal therapy during this 
study.  No other anticancer therapy will be allowed during the study.  As stated above, patients 
will continue to receive NOX66 on a cyclical basis until disease progression, unacceptable 
toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by 
the Investigator or the defined end of study is reached. Patients will have an End of Treatment 
(EOT) Visit within 7 to 10 days after the last dose of study drug.  If a patient discontinues the 
study early (Early Discontinuation [ED]), the patient will have an ED Visit within 7 to 10 days 
after the last dose of study drug. All patients (both Part 1 and Part 2) who discontinue from study 
treatment but have not withdrawn consent, for reasons other than disease progression will be 
followed up approximately every 12 weeks (± 2 weeks) after completion of their treatment 
period. They will be required to attend the clinical unit for these 12 weekly follow-up visits for 
safety assessments and undergo imaging to assess disease response until the defined study end. 
The study will be ended and closed when the last mCRPC patient enrolled in Arm 1 of Part 2 
completes 6 months of treatment, or is withdrawn from the study, whichever is shorter.  


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Patients who have withdrawn consent in both study parts will be followed up by phone for 
adverse events (AEs)/serious adverse events (SAEs) for 30 days after the last dose of study drug 
or until resolution or stabilization of ongoing AEs/SAEs deemed at least possibly related to the 
study drug, whichever is longer.  The study schemes are provided in Figure 1–1 (Part 1) and 
Figure 1–2 (Part 2), and the Schedule of Activities is provided in Table 1-1 (Parts 1 and 2). 
Part 1 (Dose Escalation) 
Approximately 30 patients with any solid tumor who require low-dose EBRT will be enrolled 
sequentially to the four planned NOX66 dose groups (Dose Cohort 1: 800 mg [3 to 6 patients]; 
Dose Cohort 2: 1200 mg; Dose Cohort 3: 1600 mg; Dose Cohort 4: 2400 mg [3 to 8 patients in 
each of Dose Cohorts 2 to 4]; total daily dose administered twice a day [BID]).  At least 
2 patients enrolled in Dose Cohorts 2 to 4 must have mCRPC. 
The proposed dose regimen for Part 1 is given in the table below.  No intra-subject dose 
escalation is allowed. 
Proposed Doses for NOX66 (Part 1) 
 
Dose Cohort 
1 
2 
3 
4 
Total daily dose 
800 mg 
1200 mg 
1600 mg 
2400 mg 
Dosing regimen 
400 mg BID 
600 mg BID 
800 mg BID 
1200 mg BID 
Number of suppositories per 
day 
2 × 400 mg 
2 × 600 mg 
4 × 400 mg 
4 × 600 mg 
BID = twice daily 
All patients will be closely monitored for any dose-limiting toxicities (DLTs) up to Day 21 of 
Cycle 1. 
Dose escalation will be based on an adapted “3+3” design, where dose cohorts will be expanded 
for up to 6 patients (Dose Cohort 1) in the event of DLT or up to 8 patients (Dose Cohorts 2 to 4) 
to allow for robust estimation of PK parameters after being deemed “safe” based on the 
traditional “3+3” design. 
At each dose level, 3 patients will initially be treated with NOX66. 
• 
If none of the first 3 patients enrolled in Cohort 1 experience a DLT during the first treatment 
cycle, the dose will be escalated to the next level. 


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• 
If none of the first 3 patients experience a DLT during the first treatment cycle of Cohorts 2 
to 4, then the dose level will be deemed “safe” and up to 5 additional patients will be enrolled 
to the current dose level for estimation of PK parameters.  At the same time (with the 
exception of Cohort 4), the next dose level will be initiated and the first 3 patients will be 
enrolled to the escalated dose. 
• 
If 1/3 patients experience a DLT, an additional 3 patients will be enrolled.  If 1/6 patients 
experience a DLT then this dose level will be deemed “safe” and, for Cohorts 2 to 4, 2 more 
patients may be enrolled for estimation of PK parameters.  At the same time, the next dose 
level will be initiated and the first 3 patients will be enrolled to the escalated dose. 
• 
If > 1/3 or > 1/6 patients experience a DLT, then dose escalation will be halted, and the 
previous dose will be declared as the MTD. 
If the 1200 mg dose is not tolerable (i.e., 2 or more patients with DLTs), an additional 3 patients 
will be enrolled in the 800 mg dose cohort in order to declare 800 mg as the MTD (if no more 
than 1/6 patients experience a DLT). 
If no DLT is observed at 2400 mg (Dose Cohort 4), dose escalation will be stopped.  The 
proposed highest dose level (2400 mg) will be declared the RP2D. 
There will be a temporary halt for enrollment after the first 3 patients are enrolled in each cohort 
until the SSC clears that the dose level is safe to continue the dose escalation. 
During the SSC meeting for NOX66 dose escalation decision, the safety and tolerability of both 
EBRT doses (8 Gy and 20/25 Gy) will also be evaluated. 
DLT monitoring will be applicable for all patients enrolled in each cohort, including patients 
enrolled for the purpose of PK analysis; as well as the decision rule for the enrollment of 
additional PK patients (i.e., stopping dose escalation). 
Part 2 (Dose Expansion) 
Part 2 will be expanded to enroll additional patients with mCRPC (Arm 1), BC and NSCLC 
(Arm 2).  All patients will be treated with NOX66 RP2D along with low-dose EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively).  Up to a total of 40 patients will be 
recruited into Part 2, dose expansion part of this study. Arm 1 will enroll 25 mCRPC patients. 
Arm 2 is an exploratory arm to assess the preliminary effectiveness of the combination of 
NOX66 at the RP2D with EBRT in other solid tumors other than mCRPC. Up to a total of 15 
patients are to be enrolled into Arm 2, comprising a mix of BC and NSCLC patients. For Part 2 
of this study, once 25 mCRPC patients have been enrolled onto Arm 1, all additional recruitment 
into Arm 2 will also stop. 


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Eligibility Criteria: 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent 
1. Patient is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form and in this protocol. 
Type of Patient and Disease Characteristics 
2. Patient has a minimum life expectancy of 6 months. 
3. Patient is 18 years or older at the time of signing the informed consent. 
4. Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid 
tumors. 
5. Confirmed metastatic disease by imaging (e.g., bone scans, X-rays, ultrasound, computerized 
tomography, magnetic resonance imaging). 
6. Documented disease progression (e.g., based on radiographic imaging, PSA or other clinical 
parameters) following first or later lines of anticancer systemic treatment. 
7. Patient is eligible for low-dose EBRT for at least one lesion. 
8. Patients with prior RT are eligible, only if there is no potential for field overlap between the 
prior RT and the planned RT. 
9. For patients with BC or NSCLC: Patient must have at least one measurable lesion as per 
RECIST v1.1 (in Part 2 only). 
10. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
11. Adequate bone marrow function defined as: 
• 
Absolute neutrophil count ≥ 1.5 × 109/L. 
• 
Platelet count ≥ 100 × 109/L. 
• 
Hemoglobin ≥ 9.0 g/dL (with or without transfusion). 
12. Adequate renal function defined as: 
• 
Creatinine clearance as measured by the Cockcroft-Gault equation > 30 mL/min. 


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13. Adequate liver function defined as: 
• 
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN; patients with confirmed 
Gilbert’s syndrome may be included in the study). 
• 
Aspartate aminotransferase/alanine aminotransferase ≤ 2.5 × ULN (or ≤ 5 × ULN in 
patients with liver metastasis).  Elevated alkaline phosphatase is not exclusionary if due 
to the presence of bone metastasis and liver function is otherwise considered adequate in 
the Investigator’s judgement. 
Metastatic Castration-resistant Prostate Cancer 
14. Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained 
throughout the duration of the study. 
15. Patient has evidence of symptomatic and/or progressive disease.  Progressive disease is 
defined as any one of the following: 
• 
Radiographic disease progression in soft tissue (nodule or visceral metastasis) and/or 
bone with or without PSA progression.  Objective evidence of increase in radiographic 
lesions or the appearance of 2 or more new lesions 
• 
Prostate-specific antigen progression: At least 3 consecutive rising PSA levels (≥ 2 to 
5 ng/mL) separated by at least 1 week, with castrate levels of testosterone. 
Breast Cancer Patients 
16. Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen 
receptors alone).  Breast cancer patients are allowed to be on background hormonal 
treatment. 
Contraception 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
NOTE: The reliability of sexual abstinence for male or female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Male Patients: 
17. Patient must have had a vasectomy or must agree to use a highly effective contraception as 
detailed in Section 10.4 of this protocol during the treatment period and for at least 3 months 
after the last dose of study drug and refrain from donating sperm during this period. 


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Female Patients: 
18. A female patient is eligible to participate if she is not pregnant (see Section 10.4), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4. 
OR 
• 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 and not to 
donate ova during the treatment period and for at least 3 months after the last dose of 
study drug. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Patient has tumor involvement of the central nervous system. 
2. Impaired cardiac functioning or clinically significant cardiac disease, including the 
following: 
• 
Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study 
drug. 
• 
Corrected QT interval using Fridericia’s formula > 470 msec on screening ECG (average 
of triplicate measurement will be used). 
• 
Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
NOTE: Patients with a history of coronary artery disease, revascularization and/or stable 
coronary artery disease are not excluded. 
3. Uncontrolled hypertension despite two concomitant antihypertensive therapies, defined as 
supine systolic blood pressure ≥ 150 mmHg or diastolic blood pressure > 100 mmHg based 
on a mean of three measurements at approximately 2-minute intervals. 
4. Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis. 
5. Patients for whom administration of the suppositories are likely to cause pain or difficulties 
in absorption (e.g., inflamed hemorrhoids, fissures or lesions of the anus or rectum). 
6. Patients with fecal impaction or uncontrolled irritable bowel disease. 
7. Patients with inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) will be 
excluded, even if the condition is well controlled. 


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8. Active or chronic infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C.  Screening of patients with serology testing for these viruses is not required.  
However, patients who have a past history of viral hepatitis or in whom there is a current 
suspicion of viral hepatitis will have serology testing for hepatitis B and hepatitis C 
performed to determine whether there is any current evidence of ongoing infection with these 
viruses.  Patients considered to be at risk for HIV infection should have HIV testing 
performed.  If the test result is negative, the patient will be allowed to participate in the study. 
NOTE: Patients with chronic HIV infection, on ongoing treatment with anti-viral 
medications, who have an undetectable viral load are not considered to be infectious and can 
be included in this study. 
9. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory 
finding that, in the Investigator’s opinion, gives reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, render the patient at high risk from treatment complications or interferes with 
obtaining informed consent. 
10. Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard 
therapy will be excluded. 
11. Major surgery within 4 weeks or minor surgery or biopsy within 1 week of the first dose 
administration. 
12. Patients who have had RT to the region of the rectum or will require RT to the region of the 
rectum during the trial.  
NOTE: Metastatic castration-resistant prostate cancer [mCRPC] patients who have received 
prior prostate or prostate fossa radiation and radiation to nearby lymph nodes, where the 
rectum is not the target, can be included in this study. 
Prior/Concomitant Therapy 
13. Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal 
medications within 14 days before the first dose administration.  Infections (e.g., urinary tract 
infection) controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per 
institutional guidelines are acceptable. 
14. Receiving or having received anticancer treatment within the following period prior to the 
first dose administration: 
• 
Cytotoxic treatment: 3 weeks. 


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• 
Non-cytotoxic drugs, including small molecule investigational products: 3 weeks or 
5 terminal half-lives from plasma (whichever is the longest). 
• 
Biological products including investigational immune-oncology agents: 4 weeks. 
• 
Radiation with a limited field for palliation: 4 weeks. 
• 
Radiation to > 30% of the bone marrow: 4 weeks. 
• 
Lung radiation: 60 days. 
15. Patient has received corticosteroids at a dose of > 10 mg prednisone/day or equivalent for 
any reason within 4 weeks prior to receiving the first dose administration. 
16. History of hypersensitivity to active or inactive excipients of study drug or drugs with a 
similar chemical structure or class to the study drug. 
Other Exclusions 
17. Patient is not willing to use suppositories. 
18. Judgement by the Investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 
19. Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prior to Screening or 
enrollment or has clinical signs and symptoms consistent with SARS-CoV-2 infection; 
e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive SARS-CoV-2 test result within 
2 weeks prior to Screening.  Patients who had symptomatic coronavirus disease 2019 
(COVID-19) less than 1 month prior to Screening will be excluded.  If a patient has had a 
severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically 
ventilated) within 4 weeks of Screening, or have any sequelae of infection or ongoing 
infection, the patient will also be excluded.  If the patient has had recent (within previous 
14 days) exposure to someone who has COVID-19 symptoms, been in contact with someone 
who has tested positive for COVID-19 or visited a COVID-19 treatment facility, the patient 
may be re-evaluated for participation in the study after undergoing an isolation period of at 
least 10 days and having a negative SARS-CoV-2 RT-PCR test prior to enrollment. 
Disclosure Statement:  
This is an open-label, multicenter, sequential 2-part treatment study (Part 1 and Part 2). 
Number of Arms: 
The study will include 4 dose cohorts (Part 1) and 2 treatment arms (Part 2). 


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Number of Patients: 
The sample sizes selected for this study are as follows: 
• 
Part 1 (Dose Escalation): Up to 30 patients will be enrolled in Part 1, in cohorts of 3 to 
6 patients (Dose Cohort 1) or 3 to 8 patients (Dose Cohorts 2 to 4) at each specified dose. 
• 
Part 2 (Dose Expansion): A total of 40 patients will be enrolled in Part 2, with 25 mCRPC 
patients in Arm 1, and up to 15 patients in total in Arm 2 comprising a mix of BC and 
NSCLC patients. Once 25 mCRPC patients have been enrolled into Arm 1, all additional 
recruitment into Arm 2 will stop, irrespective of the number of patients enrolled. Dosing 
Groups and Duration: 
• 
Part 1: Eligible patients with any solid tumor will be enrolled in one of 4 dose cohorts: 
o Dose Cohort 1: 800 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on the number of fractions to be administered).  From Cycle 2 
onwards, 800 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 2: 1200 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1200 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 3: 1600 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1600 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 4: 2400 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
2400 mg NOX66 will be administered on Days 1 to 7. 
• 
Part 2: Eligible patients will be enrolled in 1 of 2 treatment arms: 
o Arm 1 – patients with mCRPC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 
to 11 of Cycle 1, depending on number of fractions to be administered).  From Cycle 2 
onwards, RP2D NOX66 will be administered on Days 1 to 7. 
o Arm 2 – patients with BC or NSCLC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT 
(Days 2 to 11 of Cycle 1, depending on number of fractions to be administered).  From 
Cycle 2 onwards, RP2D NOX66 will be administered on Days 1 to 7. 
Patients will have a rest period (no NOX66 administration) on Days 15 to 21 of Cycle 1 and 
Days 8 to 14 of Cycle 2 onwards (Parts 1 and 2). 


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Study Assessments: 
Efficacy will be assessed by evaluating the change from baseline PSA for patients with mCRPC.  
For all patients, DCR (as measured by complete response [CR], PR and SD) will also be 
evaluated based on change from baseline imaging using RECIST v1.1 criteria.  Bone lesions will 
be evaluated using Prostate Cancer Working Group 3 (PCWG-3) criteria.  Other assessments to 
be performed during this study are ECOG scores, pain severity, and Patient Reported Outcomes.  
Efficacy will also be evaluated by examining skeletal-related events (SREs), symptomatic 
skeletal events (SSEs), progression-free survival (PFS), overall survival (OS), and objective 
response rate. 
Safety and tolerability of NOX66 and separately for both doses of EBRT (8 Gy or 20/25 Gy) will 
be determined by AEs, treatment-emergent adverse events (TEAEs), clinical laboratory 
evaluations, vital signs, 12-lead ECGs and physical examinations.  The study will also evaluate 
DLTs during Cycle 1 of Part 1. 
Plasma PK analysis for idronoxil and selected metabolites will be performed for Part 1 (all 
patients) and Part 2 (first 10 patients enrolled irrespective of tumour type) 
Changes from baseline in the lipidomic profile, plasma levels of cytokines and chemokines (all 
sites), and circulatory tumor deoxyribonucleic acid (ctDNA; all patients participating at 
pre-selected sites only) will be assessed (Parts 1 and 2). 
Statistical Analyses: 
The main aims of the study are to assess the safety, tolerability, efficacy, PK and PD profiles of 
idronoxil (and selected metabolites) and EBRT in patients with prostate cancer and other solid 
tumors. 
Continuous data will be summarized using the number of patients (n), mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum.  Categorical data will be summarized 
using frequency tabulations (number and percentage of patients). 
Baseline will be defined as the last measurement obtained prior to the first administration of 
NOX66. 
Disposition of patients will be listed and summarized.  Patient demographics, baseline 
characteristics, concomitant medications and exposure to study drug will be listed and 
summarized for each study part by dose cohort (Part 1) or treatment arm (Part 2) using 
appropriate descriptive statistics. 


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Primary Endpoint Analyses 
The primary endpoint for Part 1 (dose escalation) is the number of DLTs, which will be used to 
estimate the MTD and select the RP2D.  This will be determined by the dose level at which no 
more than 1 out of 6 patients experiences a DLT during Cycle 1.  For assessment of DLTs, 
toxicities will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) v22.0 
or higher and graded according to National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0.  The number of DLTs experienced by a patient will be 
summarized by DLT type for each dose cohort and DLT events will be listed by patient.  The 
listing will include the description, severity and relationship of the events to study drug. 
The primary endpoint for Part 2 Arm 1 (mCRPC patients) is the proportion of patients who 
achieve ≥ 30% reduction in PSA from baseline at the end of Cycles 3 and 6.  Plasma levels of 
PSA will be collected on Day 1 of Cycles 1 to 5, every second cycle thereafter (i.e., Cycles 7, 9, 
11 etc.), and at the EOT/ED Visit. For those patients that discontinue study treatment for any 
reason other than disease progression, their PSA plasma levels will continue to be collected at 
each of the 12-weekly (±2 weeks) follow-up visits until the defined study end, which is when the 
last mCRPC patient has completed 6 months of treatment, or has been withdrawn from the study, 
whichever is shorter. The number and proportions of patients with a ≥ 30% reduction in PSA 
levels from baseline to the end of Cycles 3 and 6 (primary endpoint) and change from baseline at 
any time point (secondary endpoint) will be presented for Treatment Arm 1 along with the 
corresponding exact 95% confidence interval (CI; Clopper-Pearson). 
Secondary Endpoint Analyses 
• 
Safety Analysis 
Safety profiles will be summarized by NOX66 dose cohort and separately by EBRT dose 
cohort (Part 1) or treatment arm and separately by EBRT dose cohort (Part 2) and will be 
based on the Safety Analysis Set.  Adverse events will be coded using the MedDRA v22.0 or 
higher and will be graded according to the NCI-CTCAE v5.0.  Treatment-emergent AEs are 
defined as those AEs that either start or worsen in severity on or after the date of first 
administration of study drug and on or before 30 days after the last dose of study drug.  
Treatment-emergent AEs will be summarized by severity grade and relationship to study 
drug.  Serious AEs, serious TEAEs and TEAEs leading to discontinuation of study drug or to 
death will be presented.  Changes in clinical laboratory values, vital signs, ECGs and 
physical examinations will be summarized over time. 
• 
Efficacy Analysis 
Efficacy analysis will be conducted for the patients enrolled to Part 1 and Part 2 of the study.  
Results will be summarized by dose cohort (Part 1) or treatment arm (Part 2).   


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o PSA samples (patients with mCRPC) will be collected on Day 1 of Cycles 1 to 5, every 
second cycle thereafter (i.e., Cycles 7, 9, 11, etc.), at the EOT/ED Visit. For all patients 
including those that discontinued study treatment for any reason other than disease 
progression, their PSA plasma levels will continue to be collected at each 12-weekly (±2 
weeks) follow-up visits until the defined study end.  A PSA response will be considered 
as a PSA value reduction ≥ 30% from baseline at the end of Cycles 3 and 6.  A PSA 
reduction from baseline at any time point will also be assessed as a secondary objective. 
This will be censored at the defined study end. 
o Overall response rate, defined as the percentage of patients with CR and PR, will be 
assessed based on change from baseline imaging (RECIST v1.1 and PCWG-3 criteria for 
measurable or evaluable lesions).  The number and proportion of responders (CR and PR) 
will be presented along with the exact 95% CI (Clopper-Pearson) for the time points after 
Day 1.  Tumor imaging assessment will be continued as scheduled for the patients who 
are discontinued from the study treatment for reasons other than disease progression.  The 
best overall response (CR, PR, SD or progression) will be summarized. This will be 
censored at the defined study end. 
o Change from baseline in ECOG, pain severity and pain interference with daily activities, 
and dose and frequency of morphine administration and analgesic use will be 
summarized over time.  The number and proportion of patients with a pain response 
(≥ 2-point reduction in pain severity and no additional opioid use) will be summarized 
over time along with the exact 95% CIs (Clopper-Pearson).  The number and proportion 
of patients with SREs and/or SSEs will be summarized at each time point and presented 
along with the exact 95% CI (Clopper-Pearson). 
o Scale measures from the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire for Cancer Patients (EORTC-QLQ-C30), Brief pain 
inventory-short form (BPI-SF), Patient Experience Questionnaire (PEQ), and Functional 
Assessment of Cancer Therapy – Prostate (FACT-P; mCRPC patients only) will be 
summarized for all patients by dose at each visit as well as the change from baseline to 
each visit. 
o Survival functions will be computed for OS, PFS and PSA reduction/progression (for 
Part 2, Arm 1 only) using the Kaplan-Meier method.  Estimates of median survival times 
will be presented along with 2-sided 95% CIs.  The 25th and 75th percentiles and the range 
(minimum, maximum) will be presented as well. OS, PFS and PSA response will be 
censored at the defined study end. 


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o Duration of response is defined as the time from the first documented overall response of 
CR, PR or SD to the first documented overall response of progressive disease. Duration 
of response will be censored at the defined study end.  This will be estimated using the 
Kaplan-Meier method.  Estimates of median survival times will be presented along with 
the two-sided 95% CI.  The 25th and 75th percentiles and range (minimum, maximum) 
will also be presented. 
• 
Pharmacokinetic Analysis: 
Plasma samples will be assayed for idronoxil and up to 7 selected metabolites by validated 
high-performance liquid chromatography and mass spectrometry methodology.  Individual 
plasma concentration-time data and plasma PK parameters will be summarized using 
descriptive statistics by treatment day and sampling time for idronoxil and the 7 detectable 
metabolites (GIS/SIG, IG, GI, IS, SI, SIS, and GIG).  Plasma PK parameters will be 
determined by noncompartmental analysis for idronoxil and selected metabolites and will be 
summarized by dose and treatment day. 
o The following PK parameters will be estimated for idronoxil and the selected metabolites 
following the morning dose on Days 1, 6 and 14 of Cycle 1, as data permit: Cmax, Cmin 
(predose), Tmax, AUC(0-t), AUC(0-6), AUC(0-12), AUC(0-inf) and t½. 
o Dose proportionality will be assessed for Cmax, AUC(0-t), AUC(0-inf), AUC(0-6), and 
AUC(0-12) on Days 1, 6 and 14 of Cycle 1 for the parent compound. 
o If data permits, accumulation ratios will be calculated for parent compound and selected 
metabolites for Cmax, Cmin, AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) for Days 6 and 14 
of Cycle 1 (e.g., Day 14/Day 1 and Day 6/Day 1) and Day 8 of Cycles 2 and 3. 
o The metabolite to parent ratios will be calculated (as data permit) for Days 1, 6 and 14 of 
Cycle 1, for AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) and for single time points on 
Day 1 of Cycles 2 and 3. 
Plasma concentration and PK parameter data will be listed, summarized and plotted. 
There are no formal PK parameters for concentration data from Cycles 2 and 3 because these 
are single time points.  However, metabolite to parent ratios will be explored. 
Exploratory analyses of the relationship between plasma concentrations of parent drug and 
selected metabolites and/or PK parameters and AEs or PD biomarkers may be assessed by 
graphical methods and special summary tables.  Exposure-response relationship may also be 
explored.  
 


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Exploratory Endpoint Analysis 
• 
Pharmacodynamic Biomarker Analysis: 
Plasma levels of cytokines and chemokines will be evaluated as part of the PD biomarker 
analysis.  Using the plasma samples, analysis will be performed for ctDNA and lipidomic 
profiling (capturing over 300 lipid species as determined by liquid chromatography-tandem 
mass spectrometry).  Absolute and change from baseline results of biomarker analysis will be 
summarized descriptively and also presented on a plot. 
All statistical analysis will be performed using Statistical Analysis Software® Version 9.3 or 
higher.  Further details regarding statistical analyses will be provided in the statistical analysis 
plan. 
• The efficacy endpoint for Part 2 Arm 2 (BC and NSCLC patients) is DCR assessed by 
determining the percentage of patients with the best overall response of CR or PR at any time 
plus SD from the first dose administration until disease progression, death due to any cause 
or the start of new anticancer therapy, respectively.  This will be censored at the defined 
study end. RECIST v1.1 criteria will be applied to assess CR, PR and SD.  Disease control 
rate will be presented for Treatment Arm 2 along with the corresponding exact 95% CI 
(Clopper-Pearson).  Tumor imaging and disease response assessments will be performed up 
to the time of defined study end, which is when the last mCRPC patient in Arm 1 of Part 2 
has completed 6 months of treatment.  
Data Monitoring Committee:  
A Data Monitoring Committee will not be appointed.  Patient safety and scientific integrity of 
the study will be monitored by the SSC. 


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1.2 Schema 
Figure 1–1: 
Study Design: Part 1 
 
 
 
 
TREATMENT PERIOD* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1: Days 1 to 14 
 
NOX66 
• 
Dose Cohort 1 800 mg 
NOX66† 
• 
Dose Cohort 2: 1200 mg 
NOX66 
• 
Dose Cohort 3: 1600 mg 
NOX66 
• 
Dose Cohort 4: 2400 mg 
NOX66 
(Up to 6 patients for Dose 
Cohort 1 and up to 8 patients for 
Dose Cohorts 2 to 4) 
 
Low-dose EBRT (Days 2 to11, 
depending on number of fractions to be 
administered; EBRT must start on Day 2) 
 
Cycle 1: Days 15 to 
21 
 
 
 
 
Rest Period 
 
 
 
 
 
 
Screening 
 
 
 
 
 
Days -28 
to -2 
Eligibility 
assessment 
confirmation 
(Cycle 1 
only) 
 
 
Day -1 
 
EOT/ED 
 
 
 
 
 
7-10 days 
after last 
dose 
Safety FU 
 
 
 
 
 
Up to 
30 days after 
last dose 
FU 
 
 
 
 
 
Every 
12 weeks 
(± 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 onwards: Days 1 to 7 
 
NOX66 
• 
Dose Cohort 1 800 mg 
NOX66† 
• 
Dose Cohort 2: 1200 mg 
NOX66 
• 
Dose Cohort 3: 1600 mg 
NOX66 
• 
Dose Cohort 4: 2400 mg 
NOX66 
 
 
Cycle 2 onwards: 
Days 8 to 14 
 
 
 
Rest Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Dose Escalation between Dose Cohorts 1 to 4 
 
 
800 mg NOX66 
Enroll 3 patients 
 
 
 
0 DLT 
 
1 DLT 
2 DLT 
 
Escalate to 1200 mg NOX66 
(Enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
Lower dose may be used 
   0 DLT 
1 DLT 
 
 
 
 
 
Escalate to 1600 mg NOX66 
(enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
800 mg NOX66 
 
   0 DLT 
1 DLT 
 
 
 
 
 
Escalate to 2400 mg NOX66 
(Enroll 3 patients) 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
1200 mg NOX66 
 
   0 DLT 
1 DLT 
 
 
 
 
 
Enroll 3 more patients 
 
0 DLT 
Enroll 3 more patients 
1 DLT 
MTD 
1600 mg NOX66 
  0 / 1 DLT 
2 DLT 
 
 
 
MTD 
2400 mg NOX66 
 
 
 
 
 
DLT = dose-limiting toxicity; EBRT = external beam radiotherapy; ED = early discontinuation; EOT = end of treatment; FU = Follow-up Visit; 
MTD = maximum tolerated dose 
See Section 4.1.1 and Section 7.1.2.2 for details on assessment of DLTs. 
* NOTE: Patients will receive the study drug until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, withdrawal 
of the patient by the Investigator or termination of the study by the Sponsor. 


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† Only 3 patients will be enrolled in Dose Cohort 1 (800 mg NOX66), unless there is a DLT.  If a DLT occurs, up to a maximum of 3 additional patients may be 
enrolled.  Additional patients will not be enrolled in Dose Cohort 1 for PK analysis. 
Patients who are considered evaluable for dose escalation review are 1) patients who have not experienced a DLT and has received at least 80% of the planned 
daily dose and completed all safety evaluations; 2) patients who developed DLT during the 21-day treatment cycle (Cycle 1).  For each dose cohort, at least 
3 evaluable patients are required for DLT evaluation and to make a decision on dose escalation. 
End of Treatment (EOT) Visit occurs 7 to 10 days after the last dose of study drug.  If patients discontinue the study treatment early (Early Discontinuation 
[ED]), they will have an ED Visit within 7 to 10 days after the last dose of study drug. 
Once a patient completes or discontinues study drug, he/she will be followed up every 12 weeks (± 2 weeks) after the last dose of study drug for disease 
progression and for safety until the defined study end.  
 


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Figure 1–2: 
Study Design: Part 2 
 
 
 
 
TREATMENT PERIOD* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1: Days 1 to 14 
 
NOX66 RP2D: Days 1 to 14 
 
Low-dose EBRT (Days 2 to 11, 
depending on number of fractions to be 
administered; EBRT must start on Day 2) 
 
Cycle 1: Days 15 to 
21 
 
 
 
 
Rest Period 
 
 
 
 
 
 
Screening 
 
 
 
 
 
Days -28 
to -2 
Eligibility 
assessment 
confirmation 
(Cycle 1 
only) 
 
 
Day -1 
 
EOT/ED 
 
 
 
 
 
7-10 days 
after last 
dose 
Safety FU 
 
 
 
 
 
Up to 
30 days after 
last dose 
FU 
 
 
 
 
 
Every 
12 weeks 
(± 2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 onwards: Days 1 to 7 
 
NOX66 RP2D: Days 1 to 7 
 
Cycle 2 onwards: 
Days 8 to 14 
 
 
 
Rest Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BC = breast cancer; EBRT = external beam radiotherapy; ED = early discontinuation; EOT = end of treatment; FU = Follow-up Visit; mCRPC = metastatic 
castration-resistant prostate cancer; NSCLC = non-small-cell lung cancer 
Patient population: 
• 
Arm 1: mCRPC patients only (25 patients) 
• 
Arm 2: Patients with BC and NSCLC (Up to a total of 15 patients comprising both BC and NSCLC. Recruitment into Arm 2 will stop, irrespective of 
the number of patients enrolled when 25 patients have been enrolled into Arm 1)  
End of Treatment (EOT) Visit occurs 7 to 10 days after the last dose of study drug.  If patients discontinue the study early (Early Discontinuation [ED]), they will 
have an ED Visit within 7 to 10 days after the last dose of study drug. 
Once a patient completes or discontinues study drug but has not withdrawn consent, he/she will be followed up every 12 weeks (± 2 weeks) after the last dose of 
study drug for disease progression and for safety assessment until the defined study end.  
* NOTE: Patients will receive the study drug until disease progression, unacceptable toxicity, withdrawal of consent, start of new anticancer therapy, withdrawal 
of the patient by the Investigator or defined study end.  


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1.3 Schedule of Activities 
Table 1-1 
Schedule of Activities (SoA) – Part 1 and Part 2 
Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Informed consent c 
X 
 
 
 
 
 
 
In-house stay (optional) 
 
 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Patient Diary d 
 
 
X 
X 
X 
X 
 
Phone call e 
X 
X 
X 
X 
X 
X 
X 
Routine Clinical Procedures 
Demographics 
X 
 
 
 
 
 
 
Medical history (including any available historical 
genetic assays conducted to identify genetic variations 
[all patients] and Gleason score for mCRPC patients 
only) f 
X 
X 
 
 
 
 
 
Physical examination g 
X 
 
X 
 
 
 
 
Height and weight g 
X 
 
 
 
 
 
 
Vital signs h 
X 
 
X 
X 
 
X 
 
ECG i 
X 
 
X 
X 
 
X 
 
Prior and concomitant medications j 
X 
X 
X 
X 
 
X 
 


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Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Routine Safety Measure 
Urinalysis k 
X 
 
X 
X 
 
X 
 
Hematology k, l 
X 
 
X 
X 
 
X 
 
Clinical chemistry k, m 
X 
 
X 
X 
 
X 
 
Coagulation k, n 
X 
 
X 
X 
 
X 
 
Testosterone (mCRPC) o 
X 
 
X 
 
 
 
 
Serology screen p 
X 
 
 
 
 
 
 
SARS-CoV-2 screen (optional; at Investigator’s 
discretion) q 
X 
 
 
 
 
 
 
FSH testing r 
X 
 
 
 
 
 
 
Pregnancy test s 
X 
 
X 
 
 
 
 
Adverse event t 
X 
X 
X 
X 
 
X 
 
Efficacy Measurements 
PSA u 
X 
 
X 
 
 
 
 
Tumor imaging (RECIST v1.1) CT/MRI v 
X 
 
 
 
 
 
 
Bone scan (PCWG-3) v 
X 
 
 
 
 
 
 
SRE and SSE evaluation 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
 
X 
 
 
 
 
EORTC-QLQ-C30 w 
X 
 
 
 
 
 
 
BPI-SF questionnaire w 
X 
 
 
 
 
 
 
FACT-P (mCRPC patients only) w 
X 
 
 
 
 
 
 
PEQ x 
 
 
 
X 
 
 
 
Survival status y 
 
 
 
 
 
 
 
Pharmacokinetic Measurement 
Blood sample for PK z 
 
 
X 
X 
 
X 
X 


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Procedure/Assessment 
Screening 
Cycle 1† 
Treatment Period 
Rest Period 
Day(s) 
-28 to -2 
-1 
1 
2 to 7 
8 to 13 
14 
15 to 21 
Week(s) 
-4 to 0 
1 
2 
3 
Pharmacodynamic Biomarker Assessment 
Blood sample for biomarkers aa 
X 
 
X 
 
 
 
X z 
Archived tissue collection if available (Optional) bb 
X 
 
 
 
 
 
 
Fresh tissue biopsy after Cycle 3 treatment (Optional) 
bb 
 
 
 
 
 
 
 
Treatment Administration 
NOX66 cc 
 
 
X 
X 
X 
X 
 
EBRT (1-10 days) dd 
 
 
 
X 
 
 
 
 
 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-
up/EOS b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Informed consent c 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Diary d 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Phone call e 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Routine Clinical Procedures 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
any available historical 
genetic assays conducted to 
identify genetic variations 
[all patients] and Gleason 
score for mCRPC patients 
only) f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination g 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Weight g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs h 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
ECG i 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Prior and concomitant 
medications j 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-
up/EOS b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Routine Safety Measure 
Urinalysis k 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Hematology k, l 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Clinical chemistry k, m 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Coagulation k, n 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Testosterone (mCRPC) o 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Serology screen p 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 screen 
(optional; at Investigator’s 
discretion) q 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH testing r 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test s 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Adverse event t 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Efficacy Measurements 
PSA u 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Tumor imaging (RECIST 
v1.1) CT/MRI v 
 
 
 
 
 
 
X 
 
 
 
X b 
 
X 
Bone scan (PCWG-3) v 
 
 
 
 
 
 
X 
 
 
 
X b 
 
X 
SRE and SSE evaluation 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
ECOG performance status 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
EORTC-QLQ-C30 w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
BPI-SF questionnaire w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
FACT-P (mCRPC patients 
only) w 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
PEQ x 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Survival status y 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Procedure/Assessment 
Cycle 2 Onwards† 
EOT/ED a  
(7-10 days 
after last 
dose) 
Safety 
Follow-up 
(Up to 
30 days 
after last 
dose) 
Follow-
up/EOS b 
(Every 
12 weeks 
[± 2 weeks]) 
2 
3‡ 
4§ 
5 
onwards* 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Treatment 
Period 
Rest 
Period 
Day(s) 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
2 to 7 
8 to 14 
1 
Weeks 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Pharmacokinetic Measurement 
Blood sample for PK z 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Pharmacodynamic Biomarker Assessment 
Blood sample for 
biomarkers aa 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Archived tissue collection if 
available (Optional) bb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tissue biopsy after 
Cycle 3 treatment 
(Optional) bb 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment Administration 
NOX66 cc 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
EBRT (1-10 days) dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; BPI-SF = Brief Pain Inventory – Short Form; C1D1 = Cycle 1, Day 1; COVID-19 – coronavirus disease 2019; CT = computerized 
tomography; d = day(s); EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ED = Early 
Discontinuation; EORTC-QLQ-C30 = Quality of life Questionnaire for Cancer Patients; EOS = End of Study; EOT = End of Treatment; FACT-P: Functional 
Assessment of Cancer Therapy – Prostate; FSH = follicle-stimulating hormone; Gy = Gray; mCRPC = metastatic castration-resistant prostate cancer; MRI = 
magnetic resonance imaging; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; PK = pharmacokinetics; PRO = Patient 
Reported Outcome; PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SRE = skeletal-related events; SSE = symptomatic skeletal events; WBC = white blood cell; 
WOCBP = women of childbearing potential 


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† Patients will receive the study drug from Cycle 1 Day 1 and may continue to receive the study drug until disease progression, unacceptable toxicity, withdrawal 
of consent, start of new anticancer therapy, withdrawal of the patient by the Investigator or defined study end.  
‡ From Cycle 3 onwards, study drug for 2 cycles will be dispensed every second cycle (i.e., Cycles 5, 7, 9, 11 etc.).  From Cycle 5 onwards, on-site visits will 
occur on a 28-day (4 weekly) basis, i.e., patients will visit the clinical unit every second cycle.  After Cycle 5, the next on-site visit will therefore be Cycle 7, 
followed by Cycle 9, etc. until the patient completes the study treatment period or discontinues from the study, whichever comes first. 
§ The procedures listed and schedule followed for Cycle 4 will be assessed at all cycles without an on-site visit (unless otherwise specified). 
* The procedures detailed at Cycle 5 Day 1 will be performed for all subsequent on-site visits (unless otherwise specified).  Patients will continue NOX66 
administration in each cycle from Day 1 until Day 7 followed by a 7-day rest period (Days 8 to 14). 
It is important that PK sampling occurs as close as possible to the scheduled time.  In order to achieve this, other assessments scheduled at the same time may be 
initiated prior to the timepoint.  The order of assessments (as applicable to study visit) that should occur before dosing is: 1) PRO questionnaires, 2) vital signs, 
3) ECG, 4) PK sampling, 5) dose administration.  Blood sampling for safety laboratory assessments will be done prior to dosing.  The order of assessments (as 
applicable to the study visit) that should occur after dosing is: 1) vital signs, 2) ECG, 3) PK sampling.  All other procedures can be completed (as applicable to 
study visit) after the PK sample has been collected.  It is critical that the patients record the time of dose in their Patient Study Drug Administration Diary for the 
PK assessment and the site record the time of blood sampling. 
a. 
End of Treatment Visit (EOT) occurs 7 to 10 days after the last dose of study drug.  Assessments completed within 7 days prior to the last dose of study drug 
do not need to be repeated.  If a patient discontinues from the study early (Early Discontinuation [ED]), they will have an ED Visit within 7 to 10 days after 
the last dose of study drug. 
b. 
For patients who permanently discontinue study drug for any reason other than confirmed disease progression but have not withdrawn consent, safety 
assessment and tumor imaging and disease response assessments will continue to be performed every 12 weeks (± 2 weeks)  after the last dose of the study 
drug until disease progression, withdrawal of consent, initiation of new anticancer therapy, the patient is lost to follow-up or death, or defined study end, 
whichever comes first. 
• 
If a patient meets disease progression during the follow-up period according to RECIST v1.1 criteria, a tumor imaging and disease response assessment 
is not required. 
• 
If a patient permanently meets clinical disease progression during the follow-up period, a tumor imaging and disease response assessment does not need 
to be repeated if completed ≤ 28 days after the date of clinical disease progression. 
• 
Patients who have met disease progression will be contacted every 3 months for survival follow-up until the defined study end. 
c. 
An informed consent must be signed before any study procedures may be performed. 
d. 
Patients will receive a Patient Study Drug Administration Diary for each cycle.  Patients must record the date and time of each dose administration (Days 1 
to 14 [Cycle 1] and Days 1 to 7 [Cycle 2 onwards]), as well as any missed doses. 
e. 
All patients will be contacted by phone 1 day prior to every on-site visit for assessing signs and symptoms of coronavirus disease 2019 (COVID-19) and if 
they had any contact with a person who has tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  Patients will receive a 
follow-up phone call 30 days after last dose to follow-up on any ongoing AEs/SAEs. 
f. 
Medical history includes collection of data from any available historical genetic assays conducted to identify genetic variations.  For mCRPC patients 
only: Gleason score assessment will also be collected as part of the medical history of the patient. 
g. 
A complete physical examination, including weight, will be performed during the Screening Visit.  A symptom-directed physical examination will be 
performed prior to the first dose of study drug in Cycles 1 to 3, and every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.; or within 3 days before Day 1 
of the cycle) and at the EOT/ED Visit.  Abbreviated physical examinations may be conducted as needed and will focus on new symptoms and will include 


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examination of relevant systems as identified by the Investigator.  Height will only be measured at Screening only.  Weight will be measured at Screening, 
Cycles 2, 5 and every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.).  Physical examinations need to include the assessment of the perineal and anal 
region. 
h. 
Vital signs (oral or tympanic [both are accepted] temperature, pulse, respiratory rate and blood pressure) will be measured at Screening and during Cycle 1 at 
the following timepoints: predose and at 1 and 4 hours postdose on Days 1, 6 and 14.  Vital signs will be measured predose on Day 1 of Cycles 1 to 3, every 
second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
i. 
For all patients in Part 1 and the first 10 patients for Part 2 who will undergo PK sampling, a series of ECGs (in triplicate, within 1 to 2 minutes apart) will be 
collected at Screening, and at the time points listed in Table 1-2 (Cycles 1 to 3).  For patients in Part 2 who will not undergo PK sampling, a series of ECGs 
(in triplicate, within 1 to 2 minutes apart) will be collected at Screening and a single ECG will be collected predose (within 30 minutes prior to dosing to 
allow for sitting BP if needed) on Day 1 of Cycles 1 to 3.   
Electrocardiograms will be taken predose (within 30 minutes prior to dosing to allow for sitting blood pressure if needed) for all patients in both study parts 
on Day 1 of every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit.  Electrocardiograms will be obtained after 5 minutes of rest 
in the supine position. 
j. 
At each on-site visit, the study staff will question the patient about all concomitant medication used since their last on-site visit. 
k. 
For Cycle 1 Day 1 (C1D1) predose clinical laboratory evaluations (hematology, clinical chemistry, coagulation, urinalysis) may be performed within 3 days 
before the first dose of study drug and these results can be used in place of the C1D1 (predose) results.  Laboratory assessments for Cycle 1 Days 6 and 14 
should be performed on the respective days or within 1 day before dose administration on these days.  Clinical laboratory evaluations may be performed 
within 3 days before Day 1 of Cycles 2 and 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.), and at the EOT/ED Visit. 
l. 
Hematology: Complete blood count including hemoglobin, total white blood cell (WBC) count, differential WBC count and platelet count. 
m. 
Clinical chemistry: Sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, serum creatinine, bilirubin (total and direct), alkaline phosphatase, 
albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total cholesterol, uric acid, calcium, magnesium, phosphate, serum 
glucose. 
n. 
Coagulation parameters: Prothrombin time, international normalized ratio and activated partial thromboplastin time. 
o. 
Testosterone levels of ≤ 14.4 ng/dL must be maintained from baseline and throughout the study.  Testosterone levels will be measured at Screening, on Day 1 
of Cycles 1, 2 and 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
p. 
Serology: hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and human immunodeficiency virus.  Testing only applicable to patients 
who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis, or who are considered to be at risk for human 
immunodeficiency virus infection. 
q. 
Optional: SARS-CoV-2 testing to be done at Screening and additional time points.  Testing to be done if medically indicated and at the discretion of the 
Investigator.  SARS-CoV-2 testing is not required during the follow-up period.  Patients will be advised about the risks of COVID-19 infection and will be 
questioned by phone call prior to each on-site visit to assess their health and/or contact with persons who tested positive for COVID-19 infection. 
r. 
Postmenopausal women only. 
s. 
Only applicable to women of childbearing potential (WOCBP).  Serum pregnancy test to be performed at Screening and urine pregnancy test to be 
performed prior to Day 1 of Cycles 1 to 3, at every second cycle thereafter (i.e., Cycles 5, 7, 9 11 etc.) and at the EOT/ED Visit.  No pregnancy testing will 
be performed after this period.  WOCBP must continue using approved contraception methods for at least 3 months after discontinuation of the study drug.  
During the follow-up period, WOCBP will be questioned about their pregnancy status and use of contraception up to 3 months after last dose of study drug. 


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t. 
At each on-site visit the study staff will question the patient about all adverse events (AEs) experienced since their last on-site visit.  Information on AEs and 
serious adverse events (SAEs) will be collected from signing of the informed consent form until 30 days after the last dose of study drug or until resolution 
or stabilization of ongoing AEs deemed at least possibly related to the study drug, whichever is longer.  There will be a Safety Follow-up phone call to the 
patient conducted 30 days after the last dose of study drug for collection of AE/SAE information. 
u. 
Prostate-specific antigen (PSA; patients with metastatic castration-resistant prostate cancer [mCRPC] only) will have samples collected during Screening, on 
Day 1 of Cycles 1 to 5, every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at each 12-weekly (±2 weeks) Follow-up Visits for 
all patients including those who discontinue the study treatment for any reason other than disease progression.  Patients who discontinue the study drug for 
reasons other than disease progression will continue to have PSA evaluated until disease progression, withdrawal of consent, initiation of new anticancer 
therapy, death, or defined end f study, whichever comes first.  Patients who discontinue the study drug due to disease progression do not need to provide PSA 
samples during the Follow-up Visits. 
v. 
Tumor imaging and disease response assessments will be performed within 28 days prior to enrollment, every 8 weeks (± 7 days) from the first dose 
administration up to Week 26, and every 12 weeks (± 7 days) thereafter until disease progression, withdrawal of consent, initiation of new anticancer therapy, 
or death.  Patients who discontinue the study drug due to any reason other than disease progression will continue to have tumor imaging and disease response 
assessments performed every 12 weeks (± 2 weeks)  after the last dose of study drug until disease progression, withdrawal of consent, initiation of new 
anticancer therapy, the patient is lost to follow-up, death, or defined study end, whichever comes first.  Tumor imaging should ideally be performed during 
the rest period before the start of the next treatment cycle. 
• 
If a patient permanently discontinues the study drug due to disease progression according to RECIST v1.1 criteria, a tumor imaging and disease 
response assessment is not required. 
• 
If a patient permanently discontinues the study drug due to clinical disease progression, a tumor imaging and disease response assessment does not need 
to be repeated if completed ≤ 28 days of the last dose of study drug. 
Patients who permanently discontinue the study drug or the follow-up period due to withdrawal of consent, Investigator to obtain tumor imaging and conduct 
a disease assessment at the time of the ED Visit or final Follow-up Visit if the patient agrees.  A tumor imaging and disease response assessment does not 
need to be repeated if completed ≤ 28 days of the date of withdrawal of consent. 
At a minimum, imaging of the chest, abdomen and pelvis should be performed using consistent imaging modality (computerized tomography [CT] or 
magnetic resonance imaging [MRI]).  As far as possible, the same imaging method should be used for the patient throughout the study. 
w. 
Questionnaire to be completed at Screening, Day 1 of Cycle 3, Day 1 of Cycle 5 followed by every 4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.) and at 
the EOT/ED Visit.  Questionnaire to be completed prior to performing any other study visit assessments on the day of the visit. 
x. 
Questionnaire to be completed on Day 2 of Cycle 1, Day 1 of Cycle 3 and at the EOT/ED Visit.  Questionnaire to be completed prior to performing any other 
study visit assessments on the day of the visit (excluding predose clinical laboratory assessment for Cycle 1 Day 1 which may be completed within 3 days 
prior to Day 1). 
y. 
May be an in-person visit or a phone call.  Only applicable to patients who have met disease progression. This will stop at the defined study end. 
z. 
Pharmacokinetic samples are to be obtained on Days 1, 2, 6, 14 and 15 of Cycle 1, and Days 1 and 8 of Cycles 2 and 3.  See PK sampling schedule in 
Table 1-3.  For Part 2, PK sampling will only be performed for the first 10 patients enrolled irrespective of  tumor group (mCRPC, breast cancer or non-
small-cell lung cancer). 
aa. Pharmacodynamic blood samples to be collected at Screening or Cycle 1 on Days 1 and 15, prior to dosing on Day 1 of Cycle 3 (during the rest period after 
patients have completed 7-days of NOX66 treatment in Cycle 2, or predose on Day 1 of Cycle 3) and at the EOT/ED Visit.  See PD sampling schedule in 
Table 1-4. 


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bb. Patients will be asked whether they are willing to provide both archival and fresh tissue biopsy samples OR only fresh tissue biopsy if they do not have 
archival tissue samples.  Available archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  Provision of a fresh 
biopsy sample and/or an archival tissue sample is optional.  See Table 1-5. 
cc. On days when study drug and EBRT are to be administered, it is advisable that NOX66 is given at least 1 hour prior to EBRT.  Twice daily of NOX66 dosing 
should occur at least 10 hours apart.  Where 2 suppositories are administered per dosing, each suppository will be administered at least 5 minutes apart. 
dd. The recommended dose is up to 25 Gray (Gy) radiation therapy in 1 or 5 fractionated doses over 5 to 10 days (Days 2 to 11), depending on number of 
fractions to be administered, e.g., 8 Gy = 1 fraction over 1 day, 20/25 Gy = 5 fractions over 5 to 10 days.  EBRT must start on Day 2 of Cycle 1. 
 


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1.3.1 
Electrocardiogram Schedule 
Table 1-2 
Electrocardiogram Schedule: Part 1 (All Patients) and Part 2 (Only 
for First 10 Patients enrolled, irrespective of  Tumor Type) 
Sampling 
Time Point 
Cycle 1  
Day 1 
Cycle 1 
Day 2 
Cycle 1  
Day 6 
Cycle 1  
Day 14 
Cycle 2 
Day 1 
Cycle 3 
Day 1 
Predose 
X† 
X 
X† 
X† 
X† 
X† 
1 hour (+ 15 minutes) 
X 
 
X 
X 
X 
X 
2 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
3 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
4 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
6 hours (+ 15 minutes) 
X 
 
X 
X 
 
 
8 hours (+ 15 minutes) 
X a 
 
 
 
 
 
12 hours (+ 15 minutes) 
X a 
 
 
 
 
 
† Within 30 minutes prior to dosing to allow for sitting blood pressure if needed. 
a Only for Part 1. 
NOTE: For patients who will not undergo PK sampling in Part 2 of the study, a single ECG will be collected predose 
on Day 1 of each cycle up to Cycle 3. 
After Cycle 3 Day 1, ECGs will be taken predose (within 30 minutes prior to dosing to allow for sitting blood 
pressure if needed) for all patients in both study parts, on Day 1 of every second cycle thereafter (i.e., Cycles 5, 7, 9, 
11 etc.) and at the EOT/ED Visit. 
 
 


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1.3.2 
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1 
and Part 2 
Table 1-3 
Pharmacokinetic Sampling Schedule Following Morning Dose – 
Part 1 (All Patients) and Part 2 (Only for First 10 Patients enrolled 
irrespective of  Tumor Type) 
Sampling 
Time Point 
Blood 
Volume 
(mL) 
Cycle 1 
Day 1 
Cycle 1 
Day 2* 
Cycle 1 
Day 6 
Cycle 1 
Day 14 
Cycle 1 
Day 15** 
Cycle 2 
Day 1 
Cycle 2 
Day 8*** 
Cycl
e 3  
Day 
1 b 
Cycle 3  
Day 8 b, 
*** 
Predose (within 
15 minutes prior to 
dosing) 
1 × 4 
X 
X 
X 
X 
X 
X 
Xc 
X 
Xc 
0.5 hour (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
1 hour (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
2 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
X 
 
X 
 
3 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
4 hours (± 5 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
6 hours (± 10 minutes) 
1 × 4 
X 
 
X 
X 
 
 
 
 
 
8 hours (± 15 minutes)a 
1 × 4 
X 
 
 
 
 
 
 
 
 
12 hours (± 30 minutes; 
Prior to evening dose) a 
1 × 4 
X 
 
 
 
 
 
 
 
 
a.  Only for Part 1. 
b. Cycle 3 Days 1 and 8 samples only for patients in Part 2. 
c. Can be collected at home. 
* Sample to be collected approximately 12 hours post Day 1 evening dose. 
** Sample to be collected approximately 12 hours post Day 14 evening dose. 
*** Sample to be collected approximately 12 hours post Day 7 evening dose. 
 


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Table 1-4 
Pharmacodynamic Sampling Schedule – Part 1 and Part 2 (All 
Patients) 
Assay 
Blood Volume 
(mL) 
Screening/Cycle 1 
Day 1 Predose c 
Cycle 1 
Day 15 
Prior to 
Cycle 3 b 
End of Treatment/Early 
Discontinuation 
Chemokines, cytokines and 
lipids a 
1 × 4 
X 
X 
X 
X 
Circulatory tumor DNA a,d 
2 × 4 
X 
X 
X 
X 
a Plasma 
b Sample should be collected after the patient has completed 7 days of NOX66 treatment in Cycle 2 and prior to 
dosing on Day 1 of Cycle 3. 
c Baseline samples to be collected only after eligibility confirmation or on Day 1 prior to NOX66 administration. 
d Only at pre-selected sites that have peripheral blood mononuclear cell isolation capabilities in Australia and the 
United States of America. 
Table 1-5 
Optional Archival Tissue Collection and Fresh Biopsy Sampling 
Schedule – Part 1 and Part 2 (All Patients) 
Assay 
Screening 
After Cycle 3 
treatment 
Archival tissue if available (Optional) 
X 
 
Fresh biopsy (Optional) 
 
X 
NOTE: Available archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  
Provision of a fresh biopsy sample and/or an archival tissue sample is optional. 
 


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2 Introduction 
The term “study drug” throughout the protocol, refers to NOX66.  In addition, the terms 
participant and patient are used interchangeably. 
2.1 Study Rationale 
Idronoxil, which is the active ingredient of the NOX66 formulation, is a synthetic flavonoid 
derivative of genistein that inhibits external Ecto-NOX disulfide-thiol exchanger (ENOX) 2 to 
induce apoptosis2.  ENOX2 inhibition activates the sphingomyelinase pathway and deactivates 
the antiapoptotic protein kinase B (Akt) pathway, a key driver of radiotherapy resistance.  The 
targeted effect on ENOX2 has the potential to limit toxicity to non-cancer cells, which 
preferentially express ENOX1.  Previous studies have demonstrated improved radiation 
sensitivity in prostate cancer with flavonoid derivatives.  Early studies of intravenous and oral 
formulations of idronoxil were hampered by limited bioavailability.1  The Sponsor has sought to 
address the problem of extensive drug metabolism through the development of a rectal 
suppository dosage form.  With blood draining from the distal part of the rectum directly into the 
inferior vena cava, first pass liver metabolism can be avoided.  In the case of a diphenolic drug 
such as idronoxil, the bioavailability is augmented by the rectal mucosa being known to be 
devoid of transferase activity and therefore the phase II metabolism is significantly reduced.  
These two aspects combined are the basis for the rationale that idronoxil delivered via the rectum 
is subjected to less phase I and phase II metabolism than that observed for orally administered 
idronoxil.  NOX66 is a suppository dosage form of idronoxil in a proprietary fatty base 
containing a surfactant.  This formulation is novel in that a lipophilic active ingredient is 
dispersed in a lipophilic suppository base – compared with traditional suppository formulations 
whereby a hydrophilic base would normally be utilized.  Moreover, this suppository dosage form 
provides a slow and sustained release of idronoxil comparable to an intravenous infusion.2 
The first clinical study with NOX66 (NOX66-001A) was a Phase 1a/1b study in which NOX66 
was evaluated both as a monotherapy and in combination with carboplatin, in patients with 
refractory solid tumors.  Two breast cancer (BC) patients and one ovarian cancer patient enrolled 
in this study had reductions in target lesions size with one BC patient showing target lesion 
disappearance (as per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1.) at the end 
of the study. 
The NOX66-002A study evaluated NOX66 in combination with external beam radiotherapy 
(EBRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).  Twenty-five 
patients received radiation therapy and 7 to 16 days of NOX66 treatment in this study. 


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The overall radiological assessment according to RECIST v1.1 at 3 months for 19 evaluable 
patients resulted in 17 patients with disease control (1 patient in the 800 mg and 2 patients in 
1200 mg dose cohort with partial response [PR], 14 patients with stable disease [SD]) and 
2 patients, 1 each in the 400 mg and 800 mg cohorts, respectively, with disease progression.  At 
6 months and of the 15 evaluable patients, 1 continued to have PR and 60% continued to have 
SD.  There were two changes among the patients with PR in the 1200 mg cohort, with 1 patient 
not evaluable due to withdrawal and the other patient progressing to disease progression by 
RECIST v1.1 criteria while maintaining a prostate-specific antigen (PSA; 69%) and pain 
response (69% in overall pain score). 
The overall disease control rate (DCR) at 6 months was 66.6% (10/15), with 9 patients having 
SD and 1 patient PR.  The patient with PR also had a PSA decrease of 86% and a symptom 
control response of being 100% pain-free.  A clinical meaningful response in a non-irradiated 
lesion was also observed in the same patient, with a reduction in tumor size of 26.1% from 
baseline at 3 months and a continued decline to 49.3% at 6 months (abscopal response).  Four of 
15 patients had an abscopal response in non-irradiated lesions that were outside of the radiation 
field. 
NOX66 is designed to improve drug delivery and exposure of idronoxil to tumor cells.  This 
Phase 1b/Phase 2a clinical study will explore higher doses of NOX66 and expand the experience 
of NOX66 in men with mCRPC and patients with other solid tumors to determine the 
recommended Phase 2 dose (RP2D) and provide preliminary evidence on overall tumor response 
rate, survival, symptomatic relief of pain as well as other symptoms of this disease, and effects 
on PSA levels (for mCRPC patients only). 
2.2 Background 
Cancer is one of the greatest health challenges of our time with prostate cancer being the second 
most common cancer in men.  In 2018, over 1.2 million new cases of prostate cancer were 
diagnosed worldwide and there were 350 000 deaths due to the disease.3 
Traditional chemotherapy and radiotherapy are destructive treatments that, while inflicting 
damage on cancer cells, also damage other cells in the bodies of cancer patients.2  Genistein and 
its analogue daidzein are two isoflavone extracts of soy that cause a range of physiological 
effects, including regulation of the cell cycle and apoptosis and potent sensitization of cancer 
cells to radiotherapy and chemotherapy.  The active ingredient of NOX66, idronoxil, is an 
intermediate metabolite of daidzein with greater bioavailability and anticancer activity than 
genistein, making it a superior drug candidate.  Idronoxil has been demonstrated to have in vitro 
(half maximal inhibitory concentration [IC50] < 10 µM) and in vivo activity against a broad range 


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of cancer cell lines from breast, cervical, colorectal, gallbladder, head and neck, leukemia, 
melanoma, osteosarcoma, ovarian, prostate and renal origins.  By contrast, idronoxil is only 
mildly toxic to selected cell lines of non-cancerous origins.2 
The binding target of idronoxil is an enzyme present on the external membrane of cancer cells 
known as ENOX2.  This enzyme is responsible for maintaining the transmembrane electron 
potential (TMEP) of the plasma membrane.  Inhibition of ENOX2 results in the loss of TMEP, 
precipitating a build-up of protons in the plasma membrane and a catastrophic series of events in 
the sphingomyelin pathway leading to the blockage of sphingosine-1-phosphate (S1P) 
production.  ENOX2 is an oncogene whose expression is restricted to cancer cells.  As such, 
idronoxil binding is highly specific to tumor cells.2 
The primary biological effects of idronoxil stem from inhibition of the main pro-survival 
signaling checkpoints within the cancer cell, starting with S1P which is responsible for activation 
of the phosphoinositide 3-kinase (PI3) and Akt.  Depending on the degree of inhibition by 
idronoxil, the effect ranges from cell death (variously caspase-dependent and 
caspase-independent apoptosis) down to sub-lethal effects (including inhibition of resistance 
mechanisms).  Idronoxil has been shown in vitro to be highly selective for cancer cells and 
cytotoxic against multiple tumor cell lines.2 
While idronoxil displays monotherapy cytotoxicity, NOX66 is under clinical investigation as a 
sensitizer of chemotherapy and radiotherapy through its ability to block resistance mechanisms 
including deoxyribonucleic acid repair.  The degree of sensitization of chemotherapy agents, 
including carboplatin and doxorubicin, by idronoxil has been shown in vitro to be over 
2000-fold.2 
In clinical studies, orally and intravenously administered idronoxil has proven to be highly 
susceptible to phase II metabolism (believed to be > 99% in humans when dosed orally), 
resulting in extensive inactivation of the drug and limiting its clinical efficacy.  NOX66 is a 
formulation of idronoxil designed to avoid phase II metabolism thereby conserving its bioactivity 
and facilitating transport and delivery of the active form of idronoxil to tumor cells.  Rectal 
delivery reduces the possibility of phase II metabolism by bypassing first pass metabolism in the 
liver and avoiding the high level of phase II metabolic enzymes in the intestine.2 
A detailed description of the chemistry, pharmacology, efficacy and safety of NOX66 is 
provided in the Investigator’s Brochure (IB).2 


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2.3 Benefit/Risk Assessment 
Based on Phase 1 clinical studies (Study NOX66-001A [NCT02941523] and 
Study NOX66-002A [NCT03307629]) with NOX66 at dosages of 400 mg, 600 mg, 800 mg and 
1200 mg, treatment with NOX66 in combination with carboplatin (Study NOX66-001) in 
patients with solid tumors and low-dose EBRT in patients with prostate cancer 
(Study NOX66-002A) has been shown to be well tolerated with no emerging safety signals of 
concern. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of NOX66 can be found in the IB.2 
2.3.1 
Risk Assessment 
There was one treatment-emergent adverse event (TEAE), observed in Study NOX66-001A 
(patients with prostate cancer, BC, ovarian cancer, and lung cancer), of moderate (Grade 2) 
anemia possibly related to NOX66 when dosed at 800 mg as a monotherapy.  In combination 
with carboplatin the most common TEAEs of mild to severe anemia, neutropenia and 
hypocalcemia were attributed to carboplatin alone.  Of the four deaths occurring during the 
NOX66-carboplatin treatment, sudden death, in the absence of an autopsy, was conservatively 
attributed to possibly related to carboplatin and all other deaths were due to disease progression.2 
In combination with radiotherapy (Study NOX66-002A [patients with mCRPC]), AEs of mild 
dry mouth, stomatitis (oral mucositis) and fatigue, observed for patients receiving 400 mg, 
800 mg and 1200 mg NOX66, were possibly related to the treatment.2 
The majority of all other AEs were mild to moderate (Grades 1 to 2).  Excluding serious adverse 
events (SAEs), Grade 3 AEs were lymphopenia, nausea, vomiting, asthenia, elevated blood 
alkaline phosphatase, hypocalcemia, hypophosphatemia, back pain and bone pain, and spinal 
pain which were reported in 4 patients.  No Grade 4 AEs were reported.  None of these AEs were 
considered related to NOX66 by the Investigator. 
Pathmanandavel et al (2021) and Crumbaker (2020) conducted a Phase 1/2 trial of the 
combination of 177lutetium prostate-specific membrane antigen (PSMA) 617 (LuPSMA-617) in 
combination with NOX66 in men with end-stage mCRPC.  Previous trials of lutetium PSMA in 
men with mCRPC had demonstrated good safety and efficacy.  In this study, patients with 
mCRPC were administered NOX66 (400 mg to 1200 mg daily for 10 days) in combination with 
LuPSMA-617.  Results showed similar and consistent results when compared with the safety and 
tolerability profile from other studies.  The most frequent AEs were (Grade ≥ 2) anemia (n = 19), 


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fatigue (n = 9), xerostomia (n = 3), anal inflammation (n = 3), thrombocytopenia (n = 3), 
constipation (n = 1), and pneumonitis (n = 1).4 
To date the administration of NOX66 has not been associated with any increase in cardiac AEs 
and consequently has not shown any cardiac risk from initial clinical use.  There was one cardiac 
AE of pericarditis during NOX66 monotherapy which was of moderate severity and resolved.  
Cardiac monitoring and quantitative electrocardiogram (ECG) analysis before and after the 
period of dosing with NOX66 is included in the current study.2 
Patients with mCRPC participating in this study may also receive androgen deprivation therapy 
(ADT) during the study.  This standard of care (SOC) treatment has risks associated with 
receiving the treatment, however it is not foreseen that this SOC treatment will pose a higher risk 
to patients participating in this clinical study compared to other patients with mCRPC not taking 
part in this clinical study.  Patients with BC will be allowed background hormonal therapy during 
this study. 
During the study there is also the risk of spreading severe acute respiratory coronavirus 2 
(SARS-CoV-2) which is known to be transmissible via respiratory droplets.  The coronavirus 
disease 2019 (COVID-19) pandemic began in Wuhan, China, in December 2019 and became a 
global public health emergency in March 2020.  Given that the study enrolls patients with cancer 
who are in need of treatment, the protocol allows inclusion of patients with mCRPC for whom 
the Investigator determined that the risk of potential exposure to COVID-19 (e.g., as a result of 
travel to the site and considering any other co-morbidities or risk factors the patient may have) 
does not outweigh the potential benefit of receiving treatment.  Given that each site and/or 
country may be impacted differently during the COVID-19 pandemic and changes may occur at 
a rapid pace, each site should follow their own institutional guidelines, as well as making 
individual risk assessments of their sites ability to enroll and, when needed, to hold enrollment of 
patients. 
Measures to mitigate additional risks caused by the COVID-19 pandemic include: 
• 
The study is going to start enrolling only when the Sponsor and study site in collaboration 
deem it is safe to start the study.  In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic are 
lifted by the local authorities. 
• 
Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 


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• 
Patients will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat and fatigue throughout the study.  Once clinical signs 
of infection are reported by patients, the Investigator needs to determine whether samples can 
be collected, and safety data can be recorded on site.  If not, AEs and concomitant 
medications will be obtained via phone calls.  Daily body temperature measurements during 
outpatient visits will be implemented. 
• 
Confirmation of COVID-19 infection by laboratory assessment will be conducted based on 
availability (test capacity and turnaround time) of approved tests and on Investigator’s 
discretion.  This would include testing at Screening and may optionally be done at additional 
time points if the patient has been in contact with someone who tested positive or has any 
signs and/or symptoms of COVID-19 infection. 
• 
The probability of virus transmission will be controlled as much as possible by: 
o Advice for patients to adhere to local requirements for reduction of the public exposure 
while ambulatory. 
o All patients are contacted by phone 1 day prior to every visit for assessing COVID-19 
symptoms and signs and are asked not to attend the site in case of suspected COVID-19 
disease.  In addition, patients are asked for any contact with a person who has tested 
positive for SARS-CoV-2.  If applicable, patients will be referred to the local health care 
system for further follow-up and treatment. 
o Physical distancing and person-to-person contact restrictions will be applied during site 
visits. 
o Where physical distancing is not possible, personal protective equipment will be used by 
study patients (for example surgical face mask, and gloves) and staff (for example but not 
limited to masks, gloves, protectors, and medical suits) if deemed appropriate by the 
Investigators and site staff and guided by local requirements. 
• 
Patients will follow site policy in order to mitigate the additional risks caused by COVID-19.  
All medical measures, risk/benefit and restrictions associated with COVID-19 screening will 
be explained in the informed consent form (ICF). 
2.3.2 
Benefit Assessment 
Traditional cancer treatments (e.g., chemotherapy and radiotherapy) inflict damage on both 
cancer cells and healthy tissue cells as it is not target-specific.  In contrast, idronoxil has be 
shown in vitro to be highly selective for cancer cells and cytotoxic against multiple tumor cell 
lines as well as being only slightly toxic to non-cancerous cells. 


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A drawback observed in previous clinical studies with orally dosed NOX66 was its high 
susceptibility to phase II metabolism (believed to be > 99% in humans) which resulted in 
extensive inactivation of the drug and limited its clinical efficacy.  The Sponsor has sought to 
address this problem through the development of a suppository dosage form for rectal 
administration which avoids first pass liver metabolism and reduces phase II metabolism and can 
lead to greater bioavailability and clinical efficacy in patients.  Moreover, this dosage form 
provides a slow and sustained release of idronoxil compared to intravenously administered 
idronoxil. 
This study primarily aims to evaluate the safety and tolerability of NOX66 suppository dosage 
form and determining the RP2D in patients with mCRPC and other solid tumors (Part 1), and 
determining its effect on PSA response (in patients with mCRPC) and DCR (in patients with BC 
or non-small cell lung cancer [NSCLC]) as an Exploratory endpoint (Part 2).  This study will 
further inform the dose regimen to be used in further clinical development of idronoxil as a 
potential target-specific treatment for various cancers including mCRPC and other solid tumors. 
2.3.3 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to patients participating in this study, the 
potential risks identified in association with NOX66 are justified by the anticipated benefits that 
may be afforded to patients with mCRPC and other solid tumors. 
3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives and Endpoints 
Part 1 (Dose Escalation): 
The primary objective for Part 1 will be determined 
based on the count of DLTs. 
To determine the MTD and RP2D of 
NOX66 in combination with 
low-dose EBRT in patients with any 
solid tumor 
• 
MTD is defined as the dose level at which no more 
than 1 patient out of 6 experiences a DLT at the 
end of Cycle 1. 
• 
RP2D is the highest dose administered at which no 
more than 1 patient out of 6 experiences a DLT at 
the end of Cycle 1 and the dosage form, including 
the dosing frequency, is acceptable to patients. 


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Objectives 
Endpoints 
Part 2 (Dose Expansion): 
 
Arm 1: To evaluate the effect of 
NOX66 on PSA response in patients 
with mCRPC. 
 
 
• 
PSA response is defined as the proportion of 
patients with a reduction in PSA in plasma (ng/mL) 
of ≥ 30% from baseline at the end of Cycles 3 and 
6. 
• 
 
Secondary Objectives and Endpoints 
Characterize the safety and 
tolerability of NOX66 
Safety and tolerability of NOX66 as determined by 
AEs, TEAEs, clinical laboratory evaluations, vital 
signs, 12-lead ECG and physical examinations. 
Evaluate the safety and tolerability of 
both doses of EBRT 
Safety and tolerability of both doses of EBRT as 
determined by AEs, TEAEs, clinical laboratory 
evaluations, vital signs, 12-lead ECG and physical 
examinations. 
Evaluate the exposure of idronoxil 
Concentration of idronoxil and selected metabolites in 
plasma and derived PK parameters, including but not 
limited to: Cmax, Tmax, AUC(0-t), AUC(0-6), AUC(0-12), 
AUC(0-inf), Cmin and t½, as data permit. 
Evaluate the preliminary clinical 
efficacy of NOX66 plus low-dose 
EBRT in patients with mCRPC and 
other solid tumors 
Preliminary clinical efficacy as determined by: 
• 
Change from baseline in PSA (mCRPC only) at 
any time point. 
• 
Overall response rate assessed by RECIST v1.1 
criteria (all tumor types) and PCWG-3 criteria 
(mCRPC). 
• 
Duration of response (for patients with measurable 
disease). 
• 
Change from baseline ECOG scores. 
• 
Change from baseline in tumor size and number. 
• 
PFS and OS. 
Explore the effects of NOX66 on 
pain and other cancer-related signs 
and symptoms 
Effects on pain and other cancer-related signs and 
symptoms as determined by: 
• 
Change from baseline in pain scores based on the 
BPI-SF questionnaire. 
• 
SREs and SSEs. 
• 
Change of dose and frequency of morphine 
administration and analgesic use. 


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Objectives 
Endpoints 
Evaluate the QoL using PRO 
questionnaires 
QoL as assessed by: 
• 
Change from baseline in PEQ. 
• 
Change from baseline in EORTC-QLQ-C30. 
• 
Change from baseline in FACT-P (mCRPC only). 
Exploratory Objectives and Endpoints 
Characterize the relationship 
between pharmacodynamic 
biomarkers and idronoxil plasma 
concentrations (if a meaningful 
change is observed) 
• Change in biomarkers (cytokines, chemokines and 
ctDNA) from baseline. 
• Change in lipid profile from baseline. 
Part 2 – Arm 2:  
To evaluate the effect of NOX66 on 
DCR in patients with BC and 
NSCLC. 
• DCR is measured by the percentage of patients 
with a best overall confirmed response of CR or 
PR and SD. 
AE = adverse event; BC = breast cancer; BPI-SF = Brief Pain Inventory – Short Form; CR = complete response; 
ctDNA = circulatory tumor deoxyribonucleic acid; DCR = disease control rate; DLT = dose-limiting toxicity; 
EBRT = external beam radiotherapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
for Cancer Patients; FACT-P = Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic 
castration-resistant prostate cancer; MTD = maximum tolerated dose; NSCLC = non-small-cell lung cancer; 
OS =  overall survival; PCWG-3 = Prostate Cancer Working Group 3; PEQ = Patient Experience Questionnaire; 
PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial response; PRO = Patient Reported 
Outcome; PSA = prostate-specific antigen; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid 
Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; SRE = skeletal-related events; 
SSE = symptomatic skeletal events; TEAE = treatment-emergent adverse event 
 
4 Study Design 
4.1 Overall Design 
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, 
RP2D, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil 
when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) 
and patients with mCRPC, BC and NSCLC (Part 2) who are eligible for low-dose EBRT for at 
least one symptomatic or minimally symptomatic lesion (for the prevention of symptoms).  The 
study will be performed in approximately 14 sites in Australia, United States (US) and Europe.  
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion).  The study 
design allows an exploration of different doses of NOX66 (800 mg, 1200 mg, 1600 mg and 
2400 mg) with safety monitoring to ensure the safety of the patients.  A Safety Steering 
Committee (SSC) will review available safety data after the first cycle (21 days) of each dose 
cohort of NOX66 in Part 1 to determine the maximum tolerated dose (MTD)/RP2D. 


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In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day 
cycle.  From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest 
period on a 14-day cycle.  Patients will continue to receive NOX66 on a cyclical basis until 
disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer 
therapy, withdrawal of the patient by the Investigator or until the defined study end is reached.  
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gray (Gy) as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be administered on Day 2 of Cycle 1 and the remaining dose 
fractions will be given between Day 3 and Day 11.  The choice of one of the EBRT 
dose/fractions stated above will be at the discretion of the Investigator and will be determined by 
the clinical requirements of the patient.  EBRT will be administered according to the institutional 
protocol. 
Additional EBRT at the dose levels/fractions stated above may be given during the study.  
However, should additional EBRT be considered necessary during the study (Cycle 2 onwards), 
the Investigator should communicate this to the Medical Monitor for team acknowledgment 
since extra doses could impact study results. 
The expected study duration for a patient from the time of Screening will be a minimum of 7 
months, unless the patient develops progressive disease sooner, but may be longer than 7 
months. The duration from Screening and initial administration of NOX66 until the last study 
visit is determined by the number of treatment cycles each patient receives plus the follow-up 
period, which is from the last dose of NOX66 until disease progression, withdrawal of consent, 
death or the defined end of study, whichever is shorter.  
There will be a Screening period of up to 27 days (Days -28 to -2).  Each patient will attend the 
study center on Day -1 of Cycle 1 for eligibility assessments and on all PK days 
(Cycle 1: Days 1, 2, 6, 14 and 15; Cycles 2 and 3: Days 1 and 8).  Patients in Part 1 may require 
an overnight stay on Day 1 of Cycle 1.  On Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3, the NOX66 morning administration will occur at the study center under medical 
supervision.  During these days blood samples for PK analysis will be collected as per the 
schedule mentioned in Table 1-3.  In addition to PK samples, patients will be monitored for 


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cardiac effects using 12-lead ECGs (Table 1-2).  NOX66 will be self-administered by the 
patients or administered by their care giver at home on all other dosing days as well as the 
evening doses of NOX66 on PK days (Cycle 1: Days 2, 6 and 14; Cycles 2 and 3: Day 1).  The 
evening dose of Day 1 of Cycle 1 (in Part 1 only) will be administered at the clinical unit.  
Patients or care givers should always wear gloves when handling and/or during administration of 
NOX66.  The use of a small amount of water-soluble lubricant is advised before rectal 
administration.  No oil- or wax-based lubricants should be used during rectal administration.  
Further administration instructions are provided in the “Instructions for Administration of 
NOX66 Suppositories” document.  Patients will also attend the study center for EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively) on Days 2 to 11 of Cycle 1 depending 
on the number of fractions to be administered.  From Cycle 2 onwards only NOX66 will be 
administered for 7 days followed by a 7-day rest period (as indicated above).  Patients with 
mCRPC may also receive ADT as maintenance therapy and patients with BC may receive 
background hormonal therapy during this study.  No other anticancer therapy will be allowed 
during the study.   
As stated above, patients will continue to receive NOX66 on a cyclical basis until disease 
progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, 
withdrawal of the patient by the Investigator or the defined end of study is reached. Patients will 
have an End of Treatment (EOT) Visit within 7 to 10 days after the last dose of study drug.  If a 
patient discontinues the study treatment early (Early Discontinuation [ED]), the patient will have 
an ED Visit within 7 to 10 days after the last dose of study drug. All patients (both Part 1 and 
Part 2) who discontinue from study treatment but have not withdrawn consent, for reasons other 
than disease progression will be followed up approximately every 12 weeks (± 2 weeks) after 
completion of their treatment period. They will be required to attend the clinical unit for these 12 
weekly follow-up visits for safety assessments and undergo imaging to assess disease response 
until the defined study end. The study will be ended and closed when the last mCRPC patient 
enrolled in Arm 1 of Part 2 completes 6 months of treatment, or is withdrawn from the study, 
whichever is shorter.  
Patients who have withdrawn consent in both study parts will be followed up by phone for 
adverse events (AEs)/serious adverse events (SAEs) for 30 days after the last dose of study drug 
or until resolution or stabilization of ongoing AEs/SAEs deemed at least possibly related to the 
study drug, whichever is longer.   


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The study will include 4 dose cohorts (Part 1) and 2 treatment arms (Part 2): 
• 
Part 1: Eligible patients with any solid tumor will be enrolled in one of 4 dose cohorts: 
o Dose Cohort 1: 800 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on the number of fractions to be administered).  From Cycle 2 
onwards, 800 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 2: 1200 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1200 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 3: 1600 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
1600 mg NOX66 will be administered on Days 1 to 7. 
o Dose Cohort 4: 2400 mg NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 to 11 of 
Cycle 1, depending on number of fractions to be administered).  From Cycle 2 onwards, 
2400 mg NOX66 will be administered on Days 1 to 7. 
• 
Part 2: Eligible patients will be enrolled in 1 of 2 treatment arms: 
o Arm 1 – patients with mCRPC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT (Days 2 
to 11 of Cycle 1, depending on number of fractions to be administered).  From Cycle 2 
onwards, RP2D NOX66 will be administered on Days 1 to 7. 
o Arm 2 – patients with BC and NSCLC: RP2D NOX66 (Days 1 to 14 [Cycle 1]) + EBRT 
(Days 2 to 11 of Cycle 1, depending on number of fractions to be administered).  From 
Cycle 2 onwards, RP2D NOX66 will be administered on Days 1 to 7. 
Patients will have a rest period (no NOX66 administration) on Days 15 to 21 of Cycle 1 and 
Days 8 to 14 of Cycle 2 onwards (Parts 1 and 2). 
The study schemes are provided in Figure 1–1 (Part 1) and Figure 1–2 (Part 2), and the Schedule 
of Activities (SoA) is provided in Table 1-1 (Parts 1 and 2). 
4.1.1 
Part 1 (Dose Escalation) 
Approximately 30 patients with any solid tumor who require low-dose EBRT will be enrolled 
sequentially to the four planned NOX66 dose groups (Dose Cohort 1: 800 mg [3 to 6 patients]; 
Dose Cohort 2: 1200 mg; Dose Cohort 3: 1600 mg; Dose Cohort 4: 2400 mg [3 to 8 patients in 
each of Dose Cohorts 2 to 4]; total daily dose administered twice a day [BID]).  At least 
2 patients enrolled in Dose Cohorts 2 to 4 must have mCRPC. 


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The proposed dose regimen for Part 1 is given in Table 4-1.  No intra-subject dose escalation is 
allowed. 
Table 4-1 
Proposed Doses for NOX66 (Part 1) 
 
Dose Cohort 
1 
2 
3 
4 
Total daily dose 
800 mg 
1200 mg 
1600 mg 
2400 mg 
Dosing regimen 
400 mg BID 
600 mg BID 
800 mg BID 
1200 mg BID 
Number of suppositories per 
day 
2 × 400 mg 
2 × 600 mg 
4 × 400 mg 
4 × 600 mg 
BID = twice daily 
All patients will be closely monitored for any dose-limiting toxicities (DLTs) up to Day 21 of 
Cycle 1. 
Dose escalation will be based on an adapted “3+3” design, where dose cohorts will be expanded 
for up to 6 patients (Dose Cohort 1) in the event of DLT or up to 8 patients (Dose Cohorts 2 to 4) 
to allow for robust estimation of PK parameters after being deemed “safe” based on the 
traditional “3+3” design. 
At each dose level, 3 patients will initially be treated with NOX66. 
• 
If none of the first 3 patients enrolled in Cohort 1 experience a DLT during the first treatment 
cycle, the dose will be escalated to the next level. 
• 
If none of the first 3 patients experience a DLT during the first treatment cycle of Cohorts 2 
to 4, then the dose level will be deemed “safe” and up to 5 additional patients will be enrolled 
to the current dose level for estimation of PK parameters.  At the same time (with the 
exception of Cohort 4), the next dose level will be initiated and the first 3 patients will be 
enrolled to the escalated dose. 
• 
If 1/3 patients experience a DLT, an additional 3 patients will be enrolled.  If 1/6 patients 
experience a DLT then this dose level will be deemed “safe” and, for Cohorts 2 to 4, 2 more 
patients may be enrolled for estimation of PK parameters.  At the same time, the next dose 
level will be initiated and the first 3 patients will be enrolled to the escalated dose. 
• 
If > 1/3 or > 1/6 patients experience a DLT, then dose escalation will be halted, and the 
previous dose will be declared as the MTD. 
If the 1200 mg dose is not tolerable (i.e., 2 or more patients with DLTs), an additional 3 patients 
will be enrolled in the 800 mg dose cohort in order to declare 800 mg as the MTD (if no more 
than 1/6 patients experience a DLT). 


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If no DLT is observed at 2400 mg (Dose Cohort 4), dose escalation will be stopped.  The 
proposed highest dose level (2400 mg) will be declared the RP2D. 
There will be a temporary halt for enrollment after the first 3 patients are enrolled in each cohort 
until the SSC clears that the dose level is safe to continue the dose escalation.  During the SSC 
meeting for NOX66 dose escalation decision, the safety and tolerability of both EBRT doses 
(8 Gy and 20/25 Gy) will also be evaluated.  For details on DLT evaluation, see Section 7.1.2.2. 
DLT monitoring will be applicable for all patients enrolled in each cohort, including patients 
enrolled for the purpose of PK analysis; as well as the decision rule for the additional PK patients 
(i.e., stopping dose escalation). 
4.1.2 
Part 2 (Dose Expansion) 
Part 2 will be expanded to enroll additional patients with mCRPC (Arm 1), BC and NSCLC 
(Arm 2).  All patients will be treated with NOX66 RP2D along with low-dose EBRT (8 Gy or 
20/25 Gy given as 1 or 5 fractionated doses, respectively). 
Part 2 will enroll 2 treatment arms: 
• 
Arm 1 (n = 25): Patients with mCRPC. 
• 
Arm 2 (n = up to 15): Patients with BC or NSCLC. 
4.2 Scientific Rationale for Study Design 
Better SOC treatments for patients with prostate cancer and patients with other solid tumors, who 
have exhausted treatments, are needed.  Based on the positive results observed in Phase 1 clinical 
studies with NOX66, further investigation is warranted. 
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion).  During 
Part 1, four dose levels of NOX66 will be examined to determine the MTD and RP2D to be used 
in further clinical development of NOX66.  In Part 2, the confirmed RP2D dose level will be 
further examined in patients with mCRPC, BC and NSCLC.  Part 2 will also examine the effect 
of NOX66 on PSA of patients with mCRPC and the tumor response in patients with BC and 
NSCLC as an Exploratory endpoint. 
Radiotherapy (i.e., low-dose EBRT) will be provided to patients during this study.  Low-dose 
EBRT is administered for the treatment of symptomatic lesions and/or to prevent asymptomatic 
lesions from becoming symptomatic.  Low-dose EBRT (8 Gy or 20/25 Gy as 1 or 5 fractionated 
doses, respectively) will be administered in this study for symptom control of lesions and 


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prevention of signs and symptoms.  The safety of the combination of NOX66 and EBRT has 
been tested in men with symptomatic mCRPC1 (see IB2 for details). 
The starting dose, dose escalation decision points and patient population size are based on 
accepted methodology for Phase 1/Phase 2 studies. 
In the previous study (NOX66-002A), the doses of 400 mg, 600 mg, 800 mg and 1200 mg of 
NOX66 were explored in combination with low-dose EBRT in patients with mCRPC.  The 
highest dose tested in this study was 1200 mg and a total of 15 patients have been treated with 
this dose.  There were no DLTs reported in that study.  Based on the NOX66-002A study safety 
and efficacy data this planned study is designed to continue the dose escalation from 
800 mg (400 mg BID) to 1200 mg (600 mg BID) to 1600 mg (800 mg BID) followed by 
2400 mg (1200 mg BID), if tolerable. 
In the previous trial, the total duration of NOX66 treatment was up to 16 days and low-dose 
EBRT of 20 Gy was given in 5 fractionated doses over 5 to 7 days.  NOX66 will be administered 
in this planned study on a 21-day cycle basis (14 days on treatment followed by 7 days off 
treatment) during Cycle 1, and on a 14-day cycle basis (7 days on treatment followed by 7 days 
off treatment) from Cycle 2 onwards.  NOX66 will be administered until disease progression, 
unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the 
patient by the Investigator or until the defined study end.  
The timings of safety and PK assessments in the study have been designed on the basis of 
non-clinical and clinical findings.  These data will be important to evaluate exposure-response 
relationships for efficacy and safety in mCRPC and other tumor types. 
As part of the clinical drug development program for NOX66, the Sponsor plans to include 
investigations into PD biomarker profiles and their relation to study drug effect at the intended 
dosage.  These biomarkers will be derived from blood samples taken during the study.  There are 
many potential benefits to this biomarker research, including the possibility to identify patients 
most likely to benefit from treatment, explain outliers and non-responders or explain adverse 
reactions related to study drug exposure.  This research may result in an understanding of the 
impact of variation between individuals and how it can be utilized to bring better drug products 
to the clinic. 


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4.3 Justification for Dose 
The selected starting dose, 800 mg NOX66 (total dose; 400 mg BID), has been used in a 
previous clinical trial (NOX66-002A) and was shown to be safe and well tolerated.  This dose 
level is the possible lowest BID dose of NOX66. 
Low-dose EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively) is 
considered SOC in this patient population.  The choice of dose/fraction is at Investigator’s 
discretion based on patient’s need.  Site will need to follow institutional practice for low-dose 
EBRT administration. 
4.4 End of Study Definition 
Study completion for this trial is defined as the time when the last mCRPC patient in Arm 1 of 
Part 2 has completed 6 months of treatment or is withdrawn from the study for any reason. At 
this time, all patients who are continuing in the follow-up phase of the study will have a final 
visit scheduled, and this will be the final data collection for that patient. 
At the defined study end, a review of all the patients who are still continuing participation in the 
study will be conducted to assess how many of these patients are still receiving study drug. If 
≥60% of patients are found to still be receiving study drug, these patients will be rolled into an 
Extension study where they will continue to receive study treatment. The Extension study will be 
a simple protocol to allow for study drug continuation until disease progression, withdrawal of 
consent, or death. Study follow up will consist of ongoing safety assessments and disease 
response assessment as measured by 12 weekly (±2 weeks) imaging scans. 
In the situation where at the defined end of study, ≤60% of patients are still receiving study drug, 
no Extension study will be enacted. Instead, these patients will be switched on to a 
compassionate access program and continue to receive study drug, as long as their treating 
physician believe they are continuing to receive clinical benefit. Standard pharmacovigilance 
monitoring will be put in place to continue the safety assessment of the patients still receiving 
study drug. 
5 Study Population 
The study population will consist of patients with mCRPC, BC, NSCLC or other solid tumors 
who have failed at least one line of prior treatment and for whom, according to the Investigator, 
are eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion 
(for the prevention of symptoms). 


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5.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent 
1. Patient is capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
Type of Patient and Disease Characteristics 
2. Patient has a minimum life expectancy of 6 months. 
3. Patient is 18 years or older at the time of signing the informed consent. 
4. Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid 
tumors. 
5. Confirmed metastatic disease by imaging (e.g., bone scans, X-rays, ultrasound, computerized 
tomography [CT], magnetic resonance imaging [MRI]). 
6. Documented disease progression (e.g., based on radiographic imaging, PSA or other clinical 
parameters) following first or later lines of anticancer systemic treatment. 
7. Patient is eligible for low-dose EBRT for at least one lesion. 
8. Patients with prior RT are eligible, only if there is no potential for field overlap between the 
prior RT and the planned RT. 
9. For patients with BC or NSCLC: Patient must have at least one measurable lesion as per 
RECIST v1.1 (in Part 2 only). 
10. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
11. Adequate bone marrow function defined as: 
• 
Absolute neutrophil count ≥ 1.5 × 109/L. 
• 
Platelet count ≥ 100 × 109/L. 
• 
Hemoglobin ≥ 9.0 g/dL (with or without transfusion). 
12. Adequate renal function defined as: 
• 
Creatinine clearance as measured by the Cockcroft-Gault equation > 30 mL/min. 


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13. Adequate liver function defined as: 
• 
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN; patients with confirmed 
Gilbert’s syndrome may be included in the study). 
• 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (or 
≤ 5 × ULN in patients with liver metastasis).  Elevated alkaline phosphatase is not 
exclusionary if due to the presence of bone metastasis and liver function is otherwise 
considered adequate in the Investigator’s judgement. 
Metastatic Castration-resistant Prostate Cancer 
14. Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained 
throughout the duration of the study. 
15. Patient has evidence of symptomatic and/or progressive disease.  Progressive disease is 
defined as any one of the following: 
• 
Radiographic disease progression in soft tissue (nodule or visceral metastasis) and/or 
bone with or without PSA progression.  Objective evidence of increase in radiographic 
lesions or the appearance of 2 or more new lesions. 
• 
Prostate-specific antigen progression: At least 3 consecutive rising PSA levels (≥ 2 to 
5 ng/mL) separated by at least 1 week, with castrate levels of testosterone. 
Breast Cancer Patients 
16. Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen 
receptors alone).  Breast cancer patients are allowed to be on background hormonal 
treatment. 
Contraception 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
NOTE: The reliability of sexual abstinence for male or female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 


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Male Patients: 
17. Patient must have had a vasectomy or must agree to use a highly effective contraception as 
detailed in Section 10.4 of this protocol during the treatment period and for at least 3 months 
after the last dose of study drug and refrain from donating sperm during this period. 
Female Patients: 
18. A female patient is eligible to participate if she is not pregnant (see Section 10.4), not 
breastfeeding, and at least one of the following conditions applies: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4. 
OR 
• 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 and not to 
donate ova during the treatment period and for at least 3 months after the last dose of 
study drug. 
5.2 Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Patient has tumor involvement of the central nervous system. 
2. Impaired cardiac functioning or clinically significant cardiac disease, including the 
following: 
• 
Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study 
drug. 
• 
Corrected QT interval (QTc) using Fridericia’s formula (QTcF) > 470 msec on screening 
ECG (average of triplicate measurement will be used). 
• 
Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
NOTE: Patients with a history of coronary artery disease, revascularization and/or stable 
coronary artery disease are not excluded. 
3. Uncontrolled hypertension despite two concomitant antihypertensive therapies, defined as 
supine systolic blood pressure ≥ 150 mmHg or diastolic blood pressure > 100 mmHg based 
on a mean of three measurements at approximately 2-minute intervals. 


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4. Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis. 
5. Patients for whom administration of the suppositories are likely to cause pain or difficulties 
in absorption (e.g., inflamed hemorrhoids, fissures or lesions of the anus or rectum). 
6. Patients with fecal impaction or uncontrolled irritable bowel disease. 
7. Patients with inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) will be 
excluded, even if the condition is well controlled. 
8. Active or chronic infection with human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C.  Screening of patients with serology testing for these viruses is not required.  
However, patients who have a past history of viral hepatitis or in whom there is a current 
suspicion of viral hepatitis will have serology testing for hepatitis B and hepatitis C 
performed to determine whether there is any current evidence of ongoing infection with these 
viruses.  Patients considered to be at risk for HIV infection should have HIV testing 
performed.  If the test result is negative, the patient will be allowed to participate in the study. 
NOTE: Patients with chronic HIV infection, on ongoing treatment with anti-viral 
medications, who have an undetectable viral load are not considered to be infectious and can 
be included in this study. 
9. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory 
finding that, in the Investigator’s opinion, gives reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, render the patient at high risk from treatment complications or interferes with 
obtaining informed consent. 
10. Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard 
therapy will be excluded. 
11. Major surgery within 4 weeks or minor surgery or biopsy within 1 week of the first dose 
administration. 
12. Patients who have had RT to the region of the rectum or will require RT to the region of the 
rectum during the trial. 
NOTE: Metastatic castration-resistant prostate cancer [mCRPC] patients who have received 
prior prostate or prostate fossa radiation and radiation to nearby lymph nodes, where the 
rectum is not the target, can be included in this study. 


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Prior/Concomitant Therapy 
13. Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal 
medications within 14 days before the first dose administration.  Infections (e.g., urinary tract 
infection) controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per 
institutional guidelines are acceptable. 
14. Receiving or having received anticancer treatment within the following period prior to the 
first dose administration: 
• 
Cytotoxic treatment: 3 weeks. 
• 
Non-cytotoxic drugs, including small molecule investigational products: 3 weeks or 
5 terminal half-lives from plasma (whichever is the longest). 
• 
Biological products including investigational immune-oncology agents: 4 weeks. 
• 
Radiation with a limited field for palliation: 4 weeks. 
• 
Radiation to > 30% of the bone marrow: 4 weeks. 
• 
Lung radiation: 60 days. 
15. Patient has received corticosteroids at a dose of > 10 mg prednisone/day or equivalent for 
any reason within 4 weeks prior to receiving the first dose administration. 
16. History of hypersensitivity to active or inactive excipients of study drug or drugs with a 
similar chemical structure or class to the study drug. 
Other Exclusions 
17. Patient is not willing to use suppositories. 
18. Judgement by the Investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 
19. Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for 
SARS-CoV-2 prior to Screening or enrollment or has clinical signs and symptoms consistent 
with SARS-CoV-2 infection; e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive 
SARS-CoV-2 test result within 2 weeks prior to Screening.  Patients who had symptomatic 
COVID-19 disease less than 1 month prior to Screening will be excluded.  If a patient has 
had a severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically 
ventilated) within 4 weeks of Screening, or have any sequelae of infection or ongoing 
infection, the patient will also be excluded.  If the patient has had recent (within previous 
14 days) exposure to someone who has COVID-19 symptoms, been in contact with someone 


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who has tested positive for COVID-19 or visited a COVID-19 treatment facility, the patient 
may be re-evaluated for participation in the study after undergoing an isolation period of at 
least 10 days and having a negative SARS-CoV-2 RT-PCR test prior to enrollment. 
5.3 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled in the study.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities.  
Minimal information includes demography, reason for screen failure (e.g., eligibility 
requirements failed), and any SAEs will be recorded in the electronic case report form (eCRF). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  This will be assessed on a case-by-case basis and requires Sponsor and Clinical 
Research organization (CRO)’s prior approval before the patient is rescreened.  Rescreened 
patients should be assigned a different unique participant number from the initial screening.  The 
previous screening number will be noted separately for reference purposes. 
5.3.1 
Screening and Enrollment Log and Participant Identification Numbers 
The patient’s enrollment will be recorded in the Screening and Enrollment Log. 
Upon screening, each patient will receive a unique participant identification number.  Participant 
numbers must not be re-used for different patients. 
6 Study Drug 
Study drug is defined as any investigational drug(s) (including marketed product[s]) intended to 
be administered to a study participant according to the study protocol. 
On days when study drug and EBRT are to be administered, it is advised that NOX66 is given at 
least 1 hour prior to EBRT. 
6.1 Study Drug(s) Administered 
Details on study drug administered during this study are given in Table 6-1. 
 
 


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Table 6-1 
Study Drug(s) Administered 
 
Part 1 
Part 2 
Dose Cohort/ 
Arm: 
Dose  
Cohort 1 
Dose 
Cohort 2 
Dose  
Cohort 3 
Dose  
Cohort 4 
Arm 1 
Arm 2 
Drug Name: 
NOX66 
800 mg 
NOX66 
1200 mg 
NOX66 
1600 mg 
NOX66 
2400 mg 
RP2D 
RP2D 
Type: 
Small molecule 
Dosage 
Formulation: 
Suppository containing idronoxil in a lipophilic base 
Unit Dose 
Strength(s): 
400 mg or 600 mg 
Dosage Level(s): 
1 x 400 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
800 mg. 
1 x 600 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
1200 mg. 
2 x 400 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
1600 mg. 
2 x 600 mg 
suppository 
administered 
twice daily. 
Total daily 
dose of 
2400 mg. 
To be 
determined 
To be 
determined 
Route of 
Administration: 
Rectal 
Use: 
Interventional 
IMP and NIMP: 
IMP 
Sourcing: 
Provided centrally by the Sponsor. 
Dosing 
Instructions: 
Twice daily NOX66 dosing should occur at least 10 hours apart.  Where 2 suppositories are 
administered per dosing, each suppository will be administered at least 5 minutes apart.  The 
same administration schedule should be adhered to on the days when EBRT is administered.  
Patients or care givers should always wear gloves when handling and/or during 
administration of NOX66.  The use of a small amount of water-soluble lubricant is advised 
before rectal administration.  No oil- or wax-based lubricants should be used during rectal 
administration.  Patients will be provided with an “Instructions for Administration of 
NOX66 Suppositories” that contains further details. 
Packaging and 
Labeling: 
Each suppository is supplied in individually sealed PVC suppository packaging shells and 
boxed in appropriate quantities for the clinical study.  Each box will be labeled as required 
per country requirement. 
IMP = investigational medicinal product; RP2D = recommended Phase 2 dose 
 
From Cycle 3 onwards, study drug for 2 cycles will be dispensed every second cycle 
(i.e., Cycles 5, 7, 9, 11 etc.).  From Cycle 5 onwards, on-site visits will occur on a 28-day 
(4 weekly) basis, i.e., patients will visit the clinical unit every second cycle.  After Cycle 5, the 
next patient visit will therefore be Cycle 7, followed by Cycle 9, etc. until the patient completes 
the treatment period or is withdrawn. 


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In patients who have regular bowel movements (i.e., within several hours after waking), patients 
will be instructed to insert the suppository after the bowel movement.  To promote regular bowel 
movements, patients should be encouraged to consume a high fiber diet, with adequate amounts 
of water.  In those patients who are not on a regular bowel movement schedule, insertion of the 
suppository should occur at regularly scheduled times individualized for the patient (but 
approximately 10 hours apart). 
For Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 and 3 (PK days), once the suppository 
is inserted in the rectum and defecation occurs within 2 hours after the administration, the 
remaining doses should be administered at the prescribed time as scheduled.  No re-dosing is 
permitted if defecation occurs within 2 hours of administration. 
The dosing time for suppository/ies administration must be recorded by the patient in the Patient 
Study Drug Administration Diary which must be brought to the study center at each on-site visit. 
6.1.1 
Radiotherapy 
The choice of dose/fraction as stated below is Investigator’s discretion based on patient’s need.  
Sites will need to follow institutional practice and the guidance provided in Appendix 10 
(Section 10.10) for low-dose EBRT administration. 
The study population consist of patients with mCRPC, BC, NSCLC or other solid tumors who 
have failed at least one line of prior treatment and for whom, according to the Investigator, are 
eligible for low-dose EBRT for at least one symptomatic or minimally symptomatic lesion (for 
the prevention of symptoms). 
The dose levels of EBRT will be either: 
• 
8 Gy as a single fraction, or 
• 
20/25 Gy as 5 fractions given over 5 to 10 days. 
The first EBRT dose fraction must be on Day 2 of Cycle 1 and the remaining dose fractions will 
be given between Day 3 and Day 11.  The choice of one of the EBRT dose/fractions as stated 
above will be at the discretion of the Investigator and will be determined by the clinical 
requirements of the patient.  A maximum of 2 sites can be irradiated concurrently in conjunction 
with NOX66 during Cycle 1.  EBRT will be administered according to the institutional protocol. 
Additional EBRT at the dose levels/fractions stated above may be given during the study.  
However, should additional EBRT be considered necessary during the study (Cycle 2 onwards), 
the Investigator should communicate this to the Medical Monitor for team acknowledgment 
since extra doses could impact study results. 


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6.2 Preparation, Handling, Storage, and Accountability 
The Investigator or designee must maintain a log to confirm appropriate temperature conditions 
(2°C to 8°C [35.6°F to 46.4°F], away from direct light) have been maintained during transit for 
all study drug received and any discrepancies are reported and resolved before use of the study 
drug. 
Patients must be advised that during travel from the study center to their homes the study drug 
must be stored at 2°C to 8°C (35.6°F to 46.4°F), away from direct light, and they should avoid 
leaving the study drug in their vehicle on a hot day.  They should also not keep the study drug on 
their person as the study drug will melt at body temperature.  At home the study drug should be 
stored in the fridge and handled as little as possible upon administration to prevent melting.  
Further details are provided in the “Instructions for Administration of NOX66 Suppositories”. 
Only patients enrolled in the study will receive study drug and only authorized site staff will 
supply or administer study drug.  All study drugs must be stored in a secure, environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator or designated staff (where applicable) is responsible for study drug 
accountability, reconciliation and record maintenance (e.g., receipt, reconciliation and final 
disposition records). 
Further guidance and information are provided in the “Instructions for Administration of NOX66 
Suppositories” document that will be provided by the Sponsor to patients and study staff. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study.  Each site must submit a completed Participant Enrollment Form to 
the Sponsor or CRO designee for approval to patient in the study.  The Sponsor’s representative 
(Parexel) will review the information to verify that the patient meets all inclusion criteria and 
none of the exclusion criteria to determine if the patient is eligible for study participation.  The 
Investigator must not prescribe or administer the study drug until the patient has completed 
registration and has been approved to participate in the study. 
No randomization will be done for Parts 1 and 2 as patients will all receive NOX66 and EBRT 
treatment.  Therefore, patients will be enrolled sequentially in dose cohorts of Part 1 and in 
parallel for Part 2. 


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The clinical site will be assigned a unique 4-digit number and each patient will be assigned a 
unique screening number after written informed consent is obtained.  Each patient will have a 
unique identifier (6-digit number [XXXX-YY]) that combines both the site (XXXX) and 
screening number (YY).  Participant numbers will be assigned sequentially at the clinical site. 
6.4 Study Drug Compliance 
NOX66 is packaged with each suppository individually sealed in plastic packaging and boxed as 
quantities to meet the treatment needs.  The study drug is to be stored refrigerated (2°C to 8°C 
[35.6°F to 46.4°F]). 
The suppository units are packed in individually sealed PVC suppository packaging shells and 
boxed in appropriate quantities.  Label information for the primary packaging will include, but 
are not limited to the study number, name of the product, lot number, route of administration and 
Sponsor name. 
Label information for the secondary package box which contains the suppository units will 
include but are not limited to the Sponsor’s name and address, study number, name of the 
product, lot number, re-assay date, storage conditions, dosage and patient identifier. 
All dosages of NOX66 will be self-administered by the study patients or administered by a 
caregiver.  A missed dose should be taken as soon as it is noted if it has not been longer than 
2 hours.  If the period exceeds 2 hours, the missed dose should be skipped. 
When patients are dosed at the site (Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 and 3), 
they must bring the study drug received at the start of the treatment cycle to the study site and 
will administer the study drug under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents, eCRF and Patient Study 
Drug Administration Diary for treatment compliance.  The dose of study drug and study patient 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study drug. 
When NOX66 is self-administered by the patients or administered by their care giver at home 
(all dosing days except the mornings of Days 1, 2, 6 and 14 of Cycle 1 and Day 1 of Cycles 2 
and 3), compliance with study drug will be assessed at each visit.  The patient or care giver 
should use gloves for drug administration.  Compliance will be assessed by direct questioning 
and counting returned unused suppositories during the site visits and documented in the source 
documents and eCRF.  Patients will also receive a Patient Study Drug Administration Diary in 
which they must record details of each dosing (e.g., date and time of dosing, number of 


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suppositories, missed doses).  Deviation(s) from the prescribed dosage regimen should be 
recorded in the eCRF. 
A record of the number of NOX66 suppositories dispensed to and taken by each patient must be 
maintained and reconciled with study drug and compliance records for each cycle.  Actual drug 
start and stop dates, including dates for drug delays and/or dose reductions will also be recorded 
in the eCRF. 
6.5 Concomitant Therapy 
Any medication (e.g., ADT [for mCRPC patients], bisphosphonates or denosumab, pain 
medication) or vaccine (including COVID-19 vaccine, over the counter or prescription 
medicines, vitamins, and/or herbal supplements) that the patient is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor.  Please see Sections 8.2.2.4.1 and 8.2.2.4.2, respectively, 
for details on permitted and prohibited medications. 
6.6 Dose Modification 
In patients who develop significant toxicity determined to be related to NOX66 after Cycle 1, the 
Investigator may reduce the number of suppositories or the daily dose for the patient to remain in 
the study (Table 6-2). 
In the first occurrence of any AE > Grade 1 due to NOX66 (excluding Grades 1 and 2 
anal/perianal rash), NOX66 treatment will be put on hold until the AE resolves to Grade 1 after 
which dosing can be restarted with the same dose level.  If the AE occurs again, NOX66 
treatment should be put on hold until the AE resolves to Grade 1 after which dosing may be 
restarted with a lower dose, i.e., reduced number of suppositories (Table 6-3).  Grades 1 and 2 
anal/perianal rash should be managed with hydrocortisone cream; no treatment hold is required 
in these cases. 


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Table 6-2 
Dose Modification of Study Treatment NOX66 
Current Dose 
Dose Reduction 
Total Daily Dose 
Number of 
Suppositories/Day 
Total Daily Dose 
Number of 
Suppositories/Day 
800 mg 
(400 mg BID) 
2 
400 mg 
(once daily) 
1* 
1200 mg 
(600 mg BID) 
2 
600 mg 
(once daily) 
1* 
1600 mg 
(800 mg BID  
[2× 400 mg per 
administration]) 
4 
800 mg 
(400 mg BID) 
2 
2400 mg 
(1200 mg BID 
[2 × 600 mg per 
administration]) 
4 
1200 mg 
(600 mg BID) 
2 
BID = twice daily 
* To be administered during evening dosing. 
Table 6-3 
Management of NOX66 Treatment-related Toxicity 
Event (NCI-CTCAE v5.0) 
Action 
Grades 1 to 2 toxicity  
(all events) 
Investigator judgement to continue treatment or interrupt dose (maximum 
28 days), except for Day 1 of a new cycle of study treatment, as described above.  
Initiate optimal supportive care and causality investigation.  Consider resuming at 
the same dose level when toxicity has resolved or is resolving with prophylactic 
treatment (if appropriate).  If toxicity recurs on rechallenge and does not resolve 
in < 7 days despite optimal supportive care, consider a dose reduction. 
Grade 3 to 4 toxicity 
(1st event) 
Interrupt study treatment and initiate optimal supportive care and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity has 
resolved or is resolving with prophylactic treatment (Grade ≤ 2 or returns to 
baseline), consider restarting NOX66 with reduced number of suppositories per 
day and prophylactic treatment (if appropriate). 
Grade 3 toxicity 
(recurrence of the same AE) 
Interrupt study treatment and initiate optimal supportive case and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity has 
resolved or is resolving (Grade ≤1 or returns to baseline), consider restarting 
NOX66 with reduced number of suppositories per day and prophylactic treatment 
(if appropriate).  After 2 dose reductions, consider permanent discontinuation of 
NOX66 for Grade 3 events. 
Grade 4 toxicity 
(recurrence of the same AE) 
Patients should permanently discontinue NOX66 treatment. 
AE = adverse event; NCI-CTCAE = national cancer Institute-Common Terminology Criteria for Adverse Events 
 
If a perineal and/or anal rash develops (Grade 1 to 2), a topical hydrocortisone containing 
hemorrhoid cream/ointment and/or cutaneous cream should be used.  For Grade 3 to 4 perineal 
and/or anal rash, NOX66 treatment should be delayed until the rash has resolved to Grade 1 or 
completely and hydrocortisone cream should be used as appropriate.  NOX66 should also be 


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delayed if there is proctitis, rectal mucositis or an ulcer of Grade 2 or higher.  Treatment may be 
resumed when toxicity has decreased to Grade 1.  Treatment with NOX66 should also be delayed 
in the presence of anorectal infections and may be resumed after they are resolved.  See also 
Section 7.1.1 for details on handling of dose delays. 
6.6.1 
Dose Modification of Radiotherapy 
The Investigator may adjust the dose of radiotherapy based on the standard operating procedure 
(SOP) of the site if the patient experiences intolerance or severe toxicity to radiotherapy during 
the study period. 
Patients who are eligible for an additional course of radiotherapy to the same or other lesion due 
to chronic pain or new symptomatic lesion (not related to progression) may receive an additional 
course of EBRT (8 Gy or 20/25 Gy given as 1 or 5 fractionated doses, respectively).  If such a 
case occurs, it should be discussed with the Medical Monitor before administration of the 
additional course. 
6.7 Study Drug After the End of the Study 
All patients will receive NOX66 treatment from Cycle 1 until disease progression, unacceptable 
toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by 
the Investigator or defined study end,   which will be when the last patient enrolled in Part 2 
completes 6 months treatment.   
Ongoing provision of study drug is described in Section 4.4. 
7 Discontinuation of Study Drug and Participant Discontinuation 
7.1 Discontinuation of Study Drug 
7.1.1 
Safety Stopping Criteria:  
It may be necessary for a patient to permanently discontinue (definitive discontinuation) study 
drug.  If study drug is definitively discontinued, the patient will remain in the study to be 
evaluated for clinical observation and safety monitoring.  See the SoA (Table 1-1 [Parts 1 and 2]) 
for data to be collected at the time of discontinuation of study drug and follow-up and for any 
further evaluations that need to be completed. 


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Patients may be discontinued from study drug in the following situations: 
• 
Patient decision.  The patient free to discontinue study drug at any time, without prejudice to 
further treatment. 
• 
Any AE that in the opinion of the Investigator or Sponsor contraindicates dosing or meets the 
criteria for discontinuation. 
• 
Recurrence of the same Grade 3 AE, even if recurrence is at a lower dose of study drug, with 
the exemption of localized skin reactions associated with drug administration which responds 
to topical corticosteroids. 
• 
Unacceptable toxicity. 
• 
Severe noncompliance with the protocol. 
• 
Disease progression or unacceptable toxicity. 
• 
Patient started alternative anticancer therapy including another investigational agent. 
• 
Patient is lost to follow-up. 
For patients with mCRPC, study drug will not be stopped due to rises in PSA alone.  The 
Prostate Cancer Working Group 3 (PCWG-3) emphasized the importance of keeping patients on 
the study until radiographic or symptomatic progression, which better reflects the clinical course. 
7.1.1.1 
Temporary Discontinuation 
Study drug administration may be stopped temporarily (up to 21 days) due to AE(s) and will be 
restarted after the AE resolves to Grade 1.  If an AE has not resolved after this period, but the 
Investigator confirms there is clinical benefit for the patient to continue study participation, this 
period could be extended upon discussion with Medical Monitor and Sponsor.  If the AE still has 
not resolved after this extended period, and no clinical benefit was confirmed then the patient 
will be discontinued from further NOX66 administration. This patient can continue study 
participation until disease progression, withdrawal of consent, or until defined study end.. 
7.1.2 
Dose Escalation Rules and Safety Steering Committee 
A dose in which the safety stopping criteria have been met (Section 7.1.1) or where toxicity was 
observed based on the DLT assessment criteria (Section 7.1.2.2) will not be repeated and further 
dose escalation will not occur.  Where stopping criteria have not been met, the decision of the 
SSC may be to give the next intended dose, a smaller than the predefined dose increment, a 
repeated dose or to stop dosing.  There will be a temporary halt for enrollment after the first 


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3 patients are enrolled in each cohort until the SSC clears that the dose level is safe to continue 
the dose escalation. 
Measures to ensure data integrity and safety of patients will be detailed in the Data and Safety 
Monitoring Plan. 
If the Investigator, the Medical Monitor or the Sponsor becomes aware of conditions or events 
that suggest a possible hazard to patients if the clinical study continues, then the clinical study 
may be terminated after appropriate consultation among the involved parties.  The clinical study 
may be terminated at the Sponsor’s discretion also in the absence of such a finding. 
Should the study be terminated, and/or the study center closed for whatever reason, all 
documentation pertaining to the study and study drug must be returned to Sponsor.  Any actions 
of the study site required for assessing or maintaining patient safety will continue as required, 
despite termination of the study by the Sponsor. 
7.1.2.1 
Safety Steering Committee 
The safety of the patients enrolled in this study will be closely monitored on an ongoing basis by 
an SSC during dose escalation review meetings.  The SSC will review clinical data from the 
study, including safety, available efficacy and PK data (if available), and will ensure the 
appropriate selection of doses to be used in the dose escalation and dose expansion phases of the 
study.  All safety data collected up to Cycle 1 Day 21 for each patient will be reviewed. 
The SSC will consist of: 
• 
The Sponsor’s Study Team Physician or a designee. 
• 
Clinical Research Organization’s Medical Monitor, who will chair the committee. 
• 
The Investigators or a designee from every participating site, at least from sites which enroll 
patients in the respective dose cohort. 
• 
Other Sponsor and Parexel team members. 
The SSC charter will define the exact membership and who should be present for 
recommendations to be made. 
For the initiation of a new dose level, the SSC will evaluate the available safety, tolerability and 
PK data (if available) of NOX66 in combination with EBRT.  Once 3 patients have completed 
their DLT assessment period, the SSC will review and assess all available safety data to make 
recommendations regarding that dose and/or the next dose/study part.  The decisions and 


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decision-making regarding the next dose level will be documented and provided to the 
Investigators prior to dosing of new patients.  The final decision regarding dose escalation or 
dose de-escalation will be made by the SSC. 
The SSC will be responsible for the following: 
• 
Assessment of all available safety, tolerability and exposure data during the study. 
• 
Defining patients who have experienced a DLT per protocol definitions of DLT (see 
Section 7.1.2.2). 
• 
All recommendations regarding dose escalation or dose de-escalation of NOX66.  The SSC 
may recommend proceeding with dose escalation, expand the current dose level with 
additional patient enrollment or de-escalate the dose to a lower dose level. 
• 
All recommendations regarding modification of NOX66 dosing schedule, if required.  The 
SSC may recommend adjusting the NOX66 dose, dosing frequency or schedule during either 
Cycle 1 or subsequent cycles.  In this situation, the protocol must be amended. 
• 
All recommendations relating to initiation of Part 2 enrollment. 
• 
Recommendation for cessation of dose escalation. 
• 
The review of safety and tolerability of both doses of EBRT (8 Gy and 20/25 Gy 
administered as 1 or 5 fractionated doses). 
• 
All recommendations regarding the replacement of any excluded or withdrawn patients on 
study, if necessary.* 
* Any patient initiated on treatment in error (i.e., because he or she failed to meet inclusion 
and/or exclusion criteria) but meeting the criteria of an evaluable patient, will be reviewed on a 
case-by-case basis by the SSC to determine if the patient should be included or excluded in the 
recommendation for dose escalation. 
See Section 7.1.2.2 for details on DLT assessment. 
7.1.2.2 
Assessment of Dose-limiting Toxicities 
A DLT is defined as an AE that occurs during Cycle 1 (Day 1 to Day 21) that is assessed as 
unrelated to the disease, intercurrent illness or concomitant medications and that, despite optimal 
therapeutic interventions, meets any of the following criteria (judged to be associated with 
NOX66 alone or in combination with EBRT [possibly, probably or definitely related to]): 


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1. Grade 3 or higher non-hematological toxicities (excluding alopecia) with the following 
exceptions: 
a. Grade 3 nausea/vomiting or diarrhea < 72 hours with adequate antiemetic and other 
supportive care 
b. Grade 3 fatigue < 1 week 
c. Grade 3 or higher electrolyte abnormality that lasts 24 to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical drugs 
2. Grade 4 non-hematologic (non-laboratory) toxicity of any duration. 
3. Grade 3 or Grade 4 febrile neutropenia of any duration. 
4. Grade 4 neutropenia or thrombocytopenia > 5 days. 
5. Grade 3 thrombocytopenia with bleeding. 
6. Grade 3 thrombocytopenia in combination with a Grade 3 or greater blood and lymphatic 
system disorder. 
7. Grade 3 AST or ALT that is associated with a Grade 2 or greater rise in bilirubin that lasted 
for more than 7 days. 
8. Any AST or ALT > 8 × ULN regardless of duration (5 to 8 × ULN for up to 2 weeks is 
allowed). 
9. Any AE that results in a treatment delay or hold of > 14 days. 
Grading of DLTs will follow the guidelines provided by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. 
All AEs of the grades specified above count as DLTs unless they are clearly and incontrovertibly 
due to disease progression or extraneous causes. 
After all patients enrolled in a cohort complete Cycle 1, and the data from these patients are 
available, a dose escalation meeting will be conducted.  At least 3 evaluable patients are required 
in order to proceed with DLT evaluation for each cohort. 
The criteria for determination of an evaluable patient for a dose escalation decision or 
determination of the MTD, must include: 
• 
Patient who experienced a DLT during the 21-day treatment cycle (Cycle 1), or 
• 
Patient who has not experienced a DLT and has taken at least 80% of the prescribed daily 
doses of NOX66 and completed all safety evaluations. 


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For each dose escalation cohort, additional patients may be enrolled or replaced if a patient 
discontinues prior to the completion of Cycle 1 for reasons other than safety.  Patients who 
develop a DLT and discontinue treatment will not be replaced. 
If a patient develops any DLT during Cycles 2 to 6, these will be considered ‘DLT equivalent 
toxicity’ and will be recorded in the eCRF.  This information may be considered during SSC 
review to assess dose escalation. 
When a DLT occurs, the site must immediately inform Parexel who will then inform the other 
sites that a DLT has occurred and evaluate if a second DLT has occurred at any other sites. 
Assessment of toxicities and decisions about dose recommendation for Part 1 (dose escalation) 
will be made during the SSC meeting. 
7.2 Participant Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral or administrative reasons.  
The patient will be definitively discontinued from both the study drug and from the study at that 
time. 
The primary reason for a patient withdrawing prematurely should be recorded in the patient’s 
source records and on the eCRF.  In the absence of a medical contraindication or significant 
protocol violation, every effort will be made by the Investigator to keep the patient in the study.  
Patients who discontinue study drug because of an AE but agree to participate with any 
follow-up assessments will undergo the EOT/ED Visit and will be requested to return for the 
Follow-up Visits at 12-weekly intervals (±2 weeks) until the defined study end.  The Investigator 
must contact the Medical Monitor promptly when deciding if a patient should be withdrawn or if 
the patient elects to stop the study. 
Patients withdrawn from this study cannot re-enroll.  Patients who discontinue for a non-safety 
related reason may be replaced if the patient is withdrawn during Cycle 1 in Part 1.  Withdrawal 
of consent must be ascertained and documented by the Principal Investigator who must consult 
with the Medical Monitor and document the withdrawal of consent in the eCRF and in the 
medical records.  Patients will be asked about the reason(s) for withdrawal and the presence of 
any AEs.  Should the patient agree to be followed for safety information, this should be 
documented in the medical records. 


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Patients experiencing adverse reactions should be followed until the AE has resolved, stabilized 
or is no longer deemed clinically significant, as judged by the Investigator.  Appropriate 
supportive and/or definitive therapy will be administered as required. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he or she may request destruction of any samples taken 
and not tested and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA.  Refer to the SoA (Table 1-1 [Parts 1 and 2]) for data to be 
collected at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
7.3 Loss of Participants to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the patient on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the 
patient wishes to and/or should continue in the study. 
• 
In cases in which the patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (where possible, three telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the patient’s medical 
record/eCRF. 
• 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1 [Parts 1 and 2]).  
Protocol waivers or exemptions are not allowed. 


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Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study drug. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The Investigator will maintain a Screening Log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be utilized for Screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
Repeat or unscheduled samples may be taken for safety reasons. 
8.1 Efficacy Assessments 
Efficacy will be assessed by evaluating the change from baseline PSA for patients with mCRPC 
(Section 8.1.1).  For all patients, DCR (as measured by complete response [CR], PR and SD; 
Section 8.1.2) will also be evaluated based on change from baseline imaging using RECIST v1.1 
criteria.  In mCRPC patients, bone lesions will be evaluated using PCWG-3 criteria 
(Section 8.1.3).  Other assessments to be performed during this study are ECOG scores, pain 
severity (Section 8.1.4), morphine and analgesic use (Section 8.1.6) and change from baseline 
Patient Reported Outcomes (PROs) using the questionnaires listed in Section 8.1.5 for all 
patients enrolled in the study. 
Efficacy will also be assessed by looking at the skeletal-related events (SREs) and symptomatic 
skeletal events (SSEs) (Section 8.1.7), progression-free survival (PFS; Section 8.1.8), overall 
survival (OS; Section 8.1.9), and overall or objective response rate (ORR; Section 8.1.10). 


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8.1.1 
Prostate-specific Antigen (PSA) Response and Progression (mCRPC 
only) 
For patients in both Part 1 and Part 2 Arm 1, blood for PSA assessment will be collected during 
Screening, on Day 1 of Cycles 1 to 5, every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at 
the EOT/ED Visit and each 12-weekly (±2 weeks) follow-up visits until the defined study end.  
Patients who discontinue the study drug for reasons other than disease progression will continue 
to have PSA evaluated until disease progression, withdrawal of consent, initiation of new 
anticancer therapy,  death, or defined study end, whichever comes first.  Patients who 
discontinue the study drug due to disease progression do not need to provide PSA samples 
during the Follow-up Visits.  PSA will be used as a blood-based biomarker for tracking and 
monitoring the response state during the study for mCRPC. 
A PSA response will be considered as a PSA value reduction ≥ 30% from baseline at the end of 
Cycles 3 and 6.  A PSA response reduction from baseline at any time point will also be assessed 
as a secondary objective. This will be censored at the defined end of study. 
According to PCWG-3, a sequence of rising PSA values should be obtained at a minimum of 
1-week intervals with a starting value of 2.0 ng/mL.  PSA PFS is the time from first dose 
administration to PSA progression or death. This will also be censored at the defined study end. 
8.1.2 
Disease Control Rate 
Disease control rate is measured by the percentage of patients with a best overall confirmed 
response of CR or PR at any time plus SD from first dose administration until disease 
progression or death due to any cause or the start of new anticancer therapy.  CR, PR plus SD 
will be assessed based on RECIST v1.1 (Table 1-1 [Parts 1 and 2]). This will be censored at the 
defined study end. 
8.1.3 
Tumor Imaging Assessment 
In this study, the preferred assessment of soft tissue lesions is CT or MRI scans using 
RECIST v1.1 criteria and the preferred assessment method for bone lesions is bone scan using 
PCWG-3.   
Tumor imaging using RECIST v1.1 and PCWG-3 criteria will be performed  within 28 days 
prior to enrollment, every 8 weeks (± 7 days) from the first study dose administration up to Week 
26, and every 12 weeks (± 2 weeks) thereafter until disease progression (as defined by RECIST 
v1.1 and PCWG-3 criteria), withdrawal of consent, initiation of new anticancer therapy, death, or 


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defined study end.  Tumor imaging should ideally be performed during the rest period before the 
start of the next treatment cycle. 
• 
If a patient permanently discontinues the study drug due to disease progression according to 
RECIST v1.1 criteria, a tumor imaging and disease response assessment is not required. 
• 
If a patient permanently discontinues the study drug due to clinical disease progression, a 
tumor imaging and disease response assessment does not need to be repeated if completed 
≤ 28 days after the last dose of study drug. 
For patients who permanently discontinue study drug for any reason other than confirmed 
disease progression, tumor imaging and disease response assessments will continue to be 
performed every 12 weeks (± 2 weeks)  after the last dose of the study drug until disease 
progression, withdrawal of consent, initiation of new anticancer therapy, the patient is lost to 
follow-up, death, or defined study end, whichever comes first. 
• 
If a patient meets disease progression during the follow-up period according to RECIST v1.1 
criteria, a tumor imaging and disease response assessment is not required. 
• 
If a patient meets clinical disease progression during the follow-up period, a tumor imaging 
and disease response assessment does not need to be repeated if completed ≤ 28 days after 
the date of clinical disease progression. 
For patients who permanently discontinue the study drug or the follow-up period due to 
withdrawal of consent, the Investigator is to obtain tumor imaging and conduct a disease 
assessment at the time of the ED Visit or final Follow-up Visit if the patient agrees.  A tumor 
imaging and disease response assessment does not need to be repeated if completed ≤ 28 days of 
the date of withdrawal of consent. 
The same imaging method should be used for a patient throughout the study and images should 
be read on site.  In Part 2 of the study, images should read on site and also be submitted in digital 
format to a Central Imaging Provider as detailed in the Investigator Site Operations Manual. 
Baseline scans shall be assessed and any lesions which can be measured in accordance with 
RECIST v1.1 or PCWG-3 (CT or MRI) criteria will be noted as “target lesions”.  Target 
measurable lesions may either be at the site of irradiation or non-irradiation and the number of 
lesions will be capped at 10 lesions (for RECIST v1.1).  Patients with identified measurable 
target lesions will be assessed for overall response using RECIST v1.1 criteria.  In addition to 
RECIST v1.1, all measurable lesions (irradiated and non-irradiated) will be measured and 
monitored for change (including new lesions).  To identify abscopal responses, all lesions will be 
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At a minimum, imaging of the chest, abdomen and pelvis should be performed using consistent 
imaging modality (CT or MRI).  Any other areas of disease involvement should be additionally 
investigated based on the signs and symptoms of individual patients.  During the assessments, 
subsequent to baseline, any other sites at which new disease is suspected should also be 
appropriately imaged. 
Bone scans will be used for qualitative evaluation of lesions and quantitative evaluation of new 
and/or resolved lesions.  Bone scans will be assessed using PCWG-3 criteria. 
The RECIST v1.1 and PCWG-3 guidelines for measurable, non-measurable, target and non-
target lesions and the objective tumor response criteria are presented in Section 10.5. 
8.1.4 
Eastern Cooperative Oncology Group Performance Status Score 
Eastern Cooperative Oncology Group Performance Status Score5 will be evaluated by the 
Investigator at Screening, Day 1 of Cycles 1 to 3, every second cycle thereafter (i.e., Cycles 5, 7, 
9, 11 etc.) and the EOT/ED Visit (Table 1-1 [Parts 1 and 2]).  The assessment should be 
performed by the same Investigator throughout the study, whenever possible. 
Table 8-1 
Eastern Cooperative Oncology Group Performance Status Score 
Grade 
ECOG Performance Score 
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 our work of a light 
or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to a bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry out any selfcare.  Totally confined to a bed or chair. 
5 
Dead 
 
8.1.5 
Clinical Outcome Assessment 
A Clinical Outcome Assessment is any assessment that may be influenced by human choices, 
judgement or motivation and may support either direct or indirect evidence of treatment benefit.  
Patient reported outcome is one of these types of Clinical Outcome Assessments. 
Patient reported outcome, an umbrella term referring to all outcomes and symptoms, are directly 
reported by the patient.  Patient reported outcomes have become a significant endpoint when 
evaluating effectiveness of treatments in clinical trials. 


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Questionnaires are to be completed before any other study assessments performed on the day of 
the visit. 
The following PRO instruments will be administered for analysis of the PRO endpoints in this 
study: 
• 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire for Cancer Patients (EORTC-QLQ-C30) 
The EORTC-QLQ-C30 is a well-established PRO questionnaire developed to monitor 
health-related Quality of Life (QoL) outcomes among cancer patients (Section 10.6).  The 
questionnaire assesses important functioning domains (e.g., physical, emotional, social) and 
common cancer symptoms (e.g., fatigue, pain, nausea, vomiting, appetite loss).  The 
questionnaire will be completed at Screening, on Day 1 of Cycles 3 and 5, followed by every 
4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 
and 2]). 
• 
Brief Pain Inventory – Short Form (BPI-SF) 
Worst pain, general pain and pain’s interference with daily life will be assessed during the 
study drug using the BPI-SF (Section 10.7).  The questionnaire will be completed at 
Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles thereafter (e.g., Cycle 9, 
Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 and 2]).  The BPI-SF comprises a 
total of 15 items measuring 2 domains: pain severity and pain interference.  Items measuring 
pain severity (including ‘worst pain’) are rated on an 11-point numeric rating scale ranging 
from 0=No pain to 10=Pain as bad as you can imagine.  All BPI-SF items are measured using 
a 24-hour recall period. 
• 
Functional Assessment of Cancer Therapy – Prostate (FACT-P) 
The FACT-P questionnaire is a relevant, worldwide tool used for assessing the health-related 
QoL in men with prostate cancer.  The FACT-P is a 39-item questionnaire composed of the 
FACT-General (FACT-G) original subscales (Physical Well-being, Social/Family Well-being, 
Emotional Well-being and Functional Well-being) and a Prostate Cancer Subscale 
(Section 10.9).  Each item is rated on a 5-point scale ranging from 0 (not at all) to 4 (very 
much).  A higher score indicates a better QoL.  The questionnaire will be completed by 
mCRPC patients only at Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles 
thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (Table 1-1 [Parts 1 and 2]). 
• 
Patient Experience Questionnaire (PEQ) 
The Sponsor has developed a questionnaire to evaluate the patient’s experience with the 
suppository dosage form (Section 10.8). 


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The PEQ will be completed on Day 2 of Cycle 1, Day 1 of Cycle 3 and at the EOT/ED Visit 
(Table 1-1 [Parts 1 and 2]). 
8.1.6 
Morphine Administration and Analgesic Use 
The dose and frequency of morphine administration and analgesic use will be assessed at each 
on-site study visit based on the patient’s concomitant medication use assessment. 
8.1.7 
Skeletal-related Events and Symptomatic Skeletal Events Assessment 
Skeletal-related events and SSEs will be evaluated based on the patient’s clinical history and 
examinations, including but not limited to incidence of fractures and pain.  Assessments will be 
performed at each on-site study visit. 
8.1.8 
Progression-free Survival 
Progression-free survival is defined as the duration of time from first dose administration to date 
of disease progression is objectively documented prior to data cut off. Patients alive and 
progression-free at the time of data cut-off will be censored at the date last known alive.  
Progression-free survival will be assessed every 8 weeks (± 7 days) from the first dose 
administration up to Week 26, and every 12 weeks (± 2 weeks) thereafter until disease 
progression according to RECIST v1.1 criteria. This will be censored at the defined study end if 
still alive at that time point. 
8.1.9 
Overall Survival 
Overall survival is defined as time from the date of first dose administration to date of death due 
to any cause.  Patients alive at the time of data cut-off will be censored at date last known alive. 
If alive at the defined study end, it will be censored at that time point. 
8.1.10 Overall or Objective Response Rate 
Response rate is defined as the proportion of patients who have confirmed CR or PR by objective 
disease progression RECIST v1.1, as assessed by the Investigator/local radiologist.  Overall or 
ORR will be assessed every 8 weeks (± 7 days) from the first dose administration up to Week 26, 
and every 12 weeks (± 2 weeks) thereafter until disease progression. 
Complete response is defined when all target lesions present at baseline have disappeared (with 
the exception of lymph nodes which must be < 10 mm to be considered nonpathological) and no 
new lesions have developed since baseline.  A visit response of PR is defined when the sum of 
diameters of the target lesions has decreased by 30% or more compared to baseline (with no 
evidence of progression). This will be censored at the defined study end. 


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8.2 Safety Assessments 
8.2.1 
Administrative Procedures 
8.2.1.1 
Informed Consent 
Informed consent must be documented according to Section 10.1.3.  
8.2.1.2 
Participant Identification Card 
All patients will be given a patient identification card identifying them as participants in a 
research study.  The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency.  The Investigator or qualified designee will 
provide the patient with a patient identification card immediately after the patient provides 
written informed consent. 
The patient identification card also contains contact information so that a healthcare provider can 
obtain information about study drug in emergency situations where the Investigator is not 
available.  At the time of enrollment/study drug allocation, site personnel will add the study drug 
dosage to the patient identification card. 
8.2.2 
Screening and Eligibility Assessments 
8.2.2.1 
Eligibility Criteria 
All inclusion and exclusion criteria (Section 5.1 and Section 5.2) will be reviewed by the 
Investigator or designee to ensure that the patient qualifies for the study.  Review of eligibility 
criteria will be done at Screening and at the Day -1 visit. 
8.2.2.2 
Participant Demographics and Baseline Characteristics 
Demographic data will be collected including age (at the day of Screening), gender, race, 
ethnicity and baseline characteristics (e.g., tobacco and smoking history, alcohol consumption 
history) as allowed by the local regulations. 
8.2.2.3 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at Screening.  The 
medical history will collect all active and chronic conditions from each patient.  Gleason score 
will be collected as part of the medical history for patients with mCRPC only.  Details regarding 
the disease for which the patient has enrolled in this study will be recorded separately and not 


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listed as medical history.  If the patient has data available from any historical genetic assays 
conducted to identify genetic variations, this will also be collected (all patients). 
8.2.2.4 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the patient within 30 days prior to the Screening Visit. 
The Investigator or qualified designee will record medication, if any, taken by the patient during 
the study through the last visit.  Concomitant medications will be recorded for 30 days after the 
last dose of study drug (or longer if related to an SAE). 
8.2.2.4.1 
Permitted Medications 
Analgesic agents, ADT, bisphosphonates and denosumab are allowed to be used during the 
study.  The Investigator or qualified designee will review the use of analgesic agents taken by the 
patient as part of the concomitant medications review (see SoA [Table 1-1 (Parts 1 and 2)]). 
Anti-microbial agents to control infections (e.g., urinary tract infection) are allowed as per SOC 
guidelines. 
Topical hydrocortisone-containing hemorrhoid cream/ointment and/or cutaneous cream is 
allowed for the treatment of a perineal and/or anal rash and can be administered straight after 
study drug administration, and as frequently as required as per institution. 
The use of a small amount of water-soluble lubricant is advised before rectal administration.  No 
oil- or wax-based lubricants should be used during rectal administration. 
8.2.2.4.2 
Prohibited Medication 
The following medications and therapies are not allowed during the study: 
• 
Any concomitant chemotherapy. 
• 
Oral or parenteral glucocorticoids and herbs known to alter PSA levels. 
• 
Other investigational agents. 
• 
Inducers (phenobarbital) and inhibitors (valproic acid, probenecid, atazanavir, gemfibrozil, 
indinavir) of phase 2 drug metabolizing enzymes are prohibited within 14 days prior to first 
dose of NOX66 and the rest of the study. 


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• 
Based on in vitro data, idronoxil may inhibit the activity of cytochrome P450 (CYP) 2C8, 
CYP2C9, CYP2C19 and CYP3A4 enzymes in human microsomes in a range of 0.457 to 
3000 µM and concomitant medication that is metabolized by these enzymes should be used 
with caution. 
• 
The use of inhibitors of uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes should 
be avoided. 
• 
Soya contains a high proportion of isoflavones which may interfere with the bioanalytical 
assay used for detection of idronoxil (active substance), itself an isoflavone derivative, in 
plasma and urine samples, thus within 2 days prior to NOX66 administration and for the 
entire duration of the first cycle of the study, patients must be on a soya free diet.  The 
following types of foods are prohibited: edamame, meat alternatives, miso, soymilk, soy 
nuts, soy sauce (tamari, shoyu and teriyaki), tempeh, and textured soy protein.  Trace or very 
small amounts of soy in foods are permitted. 
8.2.2.5 
Calibration of Equipment 
The Investigator (or qualified designee) is responsible for ensuring that any device or instrument 
used for a clinical evaluation/test during the study that provides information about eligibility 
criteria and/or safety or efficacy parameters is suitably calibrated and/or maintained to ensure 
that the data obtained are reliable and/or reproducible.  Documentation of equipment calibration 
must be retained as source documentation at the study site. 
8.2.3 
Dose-limiting Toxicity 
See Section 7.1.2.2 for details. 
8.2.4 
Physical Examinations 
A complete physical examination will be performed at Screening.  A symptom-directed physical 
examination will be performed prior to the first dose of study drug in Cycles 1 to 3, and every 
second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.; or within 3 days before Day 1 of the cycle) 
and at the EOT/ED Visit.  Physical examinations will include, at a minimum, assessments of the 
head, eyes, ears and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, endocrine systems and 
perineal and anal region.  Physical examinations need to include the assessment of the perineal 
and anal region.  Height will be recorded at Screening only.  Weight will be measured at 
Screening, Cycles 2 and 5 and every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.). 


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Abbreviated physical examinations may be conducted as needed and will focus on new 
symptoms and will include examination of relevant systems as identified by the Investigator. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.5 
Vital Signs 
Vital signs will be assessed as specified in the SoA (Table 1-1 [Parts 1 and 2]). 
Oral or tympanic (both are acceptable) temperature, pulse, respiratory rate and blood pressure 
(BP) will be assessed at Screening and during Cycle 1 at the following timepoints: predose and at 
1 and 4 hours postdose on Days 1, 6 and 14.  Vital signs will be measured predose on Day 1 of 
Cycles 1 to 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED 
Visit. 
Blood pressure and pulse measurements will be assessed supine with a completely automated 
device.  Manual techniques will be used only if an automated device is not available or to 
confirm automated readings, as needed. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
patient in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of one pulse and 
one BP measurement (after the patient has been supine for 5 minutes). 
8.2.6 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained in Parts 1 and 2 as outlined in the SoA (Table 1-1 
[Parts 1 and 2]) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT and QTc intervals. 
For all patients in Part 1 and the first 10 patients in each tumor type for Part 2 who will undergo 
PK sampling, a series of ECGs (in triplicate, within 1 to 2 minutes apart) will be collected at 
Screening, and at the following timepoints (Table 1-2):  
• 
Cycle 1: 
o Days 1, 6 and 14: predose (within 30 minutes prior to dosing to allow for sitting BP if 
needed) and at 1, 2, 3, 4 and 6 hours postdose (+ 15 minutes).  Additionally, for Part 1 
only, ECGs will also be taken on Day 1 at 8 and 12 hours postdose (+ 15 minutes). 
o Day 2: predose. 


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• 
Cycle 2 Day 1: Predose (within 30 minutes prior to dosing to allow for sitting BP if needed) 
and at 1 hour postdose (+ 15 minutes). 
• 
Cycle 3 Day 1: Predose (within 30 minutes prior to dosing to allow for sitting BP if needed) 
and at 1 hour postdose (+ 15 minutes). 
For patients in Part 2 who will not undergo PK sampling, a series of ECGs (in triplicate, within 1 
to 2 minutes apart) will be collected at Screening, and a single ECG predose (within 30 minutes 
prior to dosing to allow for sitting BP if needed) will be collected on Day 1 of Cycles 1 to 3. 
Electrocardiograms will be taken predose (within 30 minutes prior to dosing to allow for sitting 
blood pressure if needed) for all patients in both study parts on Day 1 of every second cycle 
thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit.  Electrocardiograms will be 
obtained after 5 minutes of rest in the supine position. 
Twelve-lead ECGs will be obtained after the patient has been resting supine for at least 
5 minutes prior to the times indicated in the SoA.  All ECGs should be recorded with the patient 
in the same physical position. 
At each time point at which triplicate ECG recordings are required, three individual ECG 
tracings should be obtained as closely as possible in succession, within 1 to 2 minutes apart.  The 
full set of triplicates should be completed in less than 4 minutes. 
8.2.7 
Clinical Safety Laboratory Assessments 
Refer to Section 10.2 for the list of clinical safety laboratory tests to be performed and to the 
SoA (Table 1-1 [Parts 1 and 2]) for the timing and frequency.  Clinical laboratory assessments 
will be done at Screening, Cycle 1 on Day 1 (or within 3 days before the first dose administration 
on Day 1), Days 6 and 14 (within 1 day before dose administration on each of Days 6 and 14), on 
Day 1 (or within 3 days of Day 1) of Cycles 2 and 3, every second cycle thereafter 
(i.e., Cycles 5, 7, 9, 11 etc.) and at the EOT/ED Visit. 
The Investigator must review the laboratory report, document this review and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  The 
laboratory reports must be filed with the source documents.  Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically abnormal during the study treatment period 
or within 30 days after the last dose of study drug should be repeated until the values return to 


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normal or baseline or are no longer considered clinically significant by the Investigator or 
Medical Monitor. 
• 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, where possible, and the Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Section 10.2 must be conducted 
in accordance with the laboratory manual and the SoA. 
• 
If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in patient management or 
are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or an 
AE or require dose modification), then the results must be recorded in the eCRF. 
8.2.8 
Radiotherapy Treatment Interruptions 
The frequency of radiotherapy treatment interruptions will be assessed by calculating the number 
of days of treatment interruptions over the study. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AE that are serious, considered related to the study drug or the study, or that caused the 
patient to discontinue the study drug or the study (see Section 7). 
Adverse event questioning will include specific questions regarding symptoms of COVID-19: 
fever, cough, dry throat, difficulty breathing and potential exposure in the past 2 weeks. 
Confirmed and suspected SARS-CoV-2 infection and COVID-19 will be recorded in the AE 
fields. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the last dose 
of study drug at the time points specified in the SoA (Table 1-1 [Parts 1 and 2]).  Follow-up of 
AEs/SAEs after the last dose of study drug will be done by phone call. 


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Medical occurrences that begin before the first dose administration but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3.  The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation.  However, if the Investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.3.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
The severity of AEs will be classified into Grade 1 through 5 using the NCI-CTCAE v5.0.  For 
details, refer to Section 10.3.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrence. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, until the 
event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Section 10.3) by the Investigator to the Sponsor of an 
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study drug under clinical investigation are met. 
The Sponsor and CRO have a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical investigation.  The 


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Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC), 
and Investigators. 
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with the 
IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
If a female patient or a female partner of a male study patient who has been exposed to the study 
drug becomes pregnant, the pregnancy and outcome of pregnancy should be monitored.  If a 
pregnancy in a female patient or a female partner of a male patient is reported, the Investigator 
should inform the Sponsor within 24 hours of learning of the pregnancy and should follow the 
procedures outlined in Section 10.4. 
Pregnancy of the female patient or of the male patient’s female partner alone is not regarded as 
an AE unless there is a suspicion that the study drug may have interfered with the effectiveness 
of a contraceptive medication.  Details of all pregnancies in female patients or female partners of 
male patients will be collected after the first dose administration and until 3 months after the last 
dose of NOX66.  Information on the pregnancy of a female patient or of the male patient’s 
female partner must be obtained directly from the female patient or the male patient’s female 
partner.  Therefore, prior to obtaining information on the pregnancy, the Investigator must obtain 
the consent of the female patient or the male patient’s female partner. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions.  Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE. 
8.3.6 
Cardiovascular and Death Events 
Not applicable. 


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8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable. 
8.3.8 
Adverse Events of Special Interest 
Not applicable. 
8.4 Treatment of Overdose 
For this study, any dose of NOX66 greater than 2400 mg within a 24-hour time period will be 
considered an overdose.  If a patient takes more doses than the assigned doses within a 24-hour 
time period, this will also be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for AE/SAE and laboratory abnormalities until resolved or for up 
to 30 days (whichever occurs first). 
3. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding whether the patient can continue the study will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.5 Pharmacokinetics 
In Parts 1 and 2, blood samples of approximately 4 mL each will be collected for measurement 
of plasma concentrations of idronoxil, and selected metabolites as specified in the SoA 
(Table 1-1 [Parts 1 and 2]).  For Part 2, PK sampling will only occur for the first 10 patients 
enrolled in each tumor group (mCRPC, BC and NSCLC).  A maximum of 31 samples will be 
collected at various time points during the study (see Table 1-3 for detailed sampling schedule) 
from each patient.  Instructions for the collection and handling of PK samples will be provided in 
the laboratory manual.  The actual date and time (24-hour clock time) of each sample will be 
recorded in the eCRF.  If a bowel movement occurs during the collection period, the time of each 
bowel movement should be recorded, and the blood sample collections should continue as 


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planned.  Plasma will be analyzed for the quantification of idronoxil and selected metabolites 
using a validated high-performance liquid chromatography and mass spectrometry methodology. 
Each plasma sample will be divided into 3 aliquots (1 each for PK, other analyses, and a 
back-up) and stored according to the instructions in the Laboratory Manual.  Samples collected 
for analyses of idronoxil plasma concentration may also be used to evaluate safety or efficacy 
aspects that address concerns arising during or after the study.  Pharmacokinetic parameters of 
idronoxil and selected metabolites will be determined by non-compartmental analysis.  
Pharmacokinetic sample analysis will be performed at a designated central laboratory. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files. 
8.6 Pharmacodynamics 
Please refer to Section 8.8 Biomarkers. 
8.7 Genetics 
The study will collect data from any available historical genetic assays conducted to identify 
genetic variations as part of the patients’ medical history. 
8.8 Biomarkers 
Changes from baseline in the lipidomic profile, plasma levels of cytokines, chemokines (all sites) 
and circulatory tumor deoxyribonucleic acid (ctDNA; for all patients at pre-selected sites that 
have peripheral blood mononuclear cell isolation capabilities in Australia and the US only) will 
be assessed (Parts 1 and 2).  These sample analyses will be performed at a designated central 
laboratory.  In addition, lipidomic profiling, capturing over 300 lipid species, will be determined 
by liquid chromatography-tandem mass spectrometry on the plasma samples collected from the 
study patients.  Samples for ctDNA analysis will not be collected from patients at sites in 
countries where this is not permitted by the regulatory authorities. 
Blood samples of approximately 4 mL each will be collected for measurement of plasma 
cytokine, chemokine and lipid concentrations and approximately 10 mL each for ctDNA analysis 
as specified in Table 1-4. 
Sampling for biomarker analysis will be performed at: 
• 
Screening or Cycle 1 on Days 1 and 15 


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• 
Prior to Cycle 3 Day 1: This sample should be collected after the patient has completed 
7 days of NOX66 treatment in Cycle 2, but before Day 1 of Cycle 3. 
• 
EOT/ED Visit. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Each plasma sample will be divided into 3 aliquots (1 each for PD, other analyses, and a 
back-up) and stored according to the instructions in the Laboratory Manual. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last patient’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to NOX66. 
If there is any remaining plasma from these samples, the Sponsor may perform additional 
analyses for relevant biomarkers in the future.  Taking part in this future research is optional.  
Patients will be asked to consent to their samples being used for this optional future research. 
8.9 Archival and Fresh Tissue Biopsy 
Patients will be asked whether they are willing to provide both archival and fresh tissue biopsy 
samples OR only fresh tissue biopsy if they do not have archival tissue samples.  Available 
archival tissue samples will only be requested if a fresh tissue biopsy is collected after Cycle 3.  
Provision of a fresh biopsy sample and/or an archival tissue sample is optional.  See Table 1-5. 
8.10 Immunogenicity Assessments 
Immunoassays will not be performed during this study. 
8.11 Health Economics or Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
There will be no formal statistical hypotheses tested in this study.  All analyses will be 
descriptive. 


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9.2 Sample Size Determination 
The primary objective of this study is to characterize the safety and tolerability of NOX66 and 
thereby inform the RP2D of NOX66 for future clinical studies in patients with mCRPC and other 
solid tumors.  Hence, for Part 1 and Part 2 the number of patients has been chosen with the aim 
to obtain adequate safety, tolerability,  PK, and PD profile data while exposing as few patients as 
possible to the study treatments and procedures. 
The sample sizes selected for this study are as follows: 
• 
Part 1 (Dose Escalation): Up to 30 patients will be enrolled in Part 1, in cohorts of 3 to 
6 patients (Dose Cohort 1) or 3 to 8 patients (Dose Cohorts 2 to 4) at each specified dose. 
• 
Part 2 (Dose Expansion): Up to a total of 40 patients will be recruited into Part 2, dose 
expansion part of this study. Arm 1 will enroll 25 mCRPC patients. Arm 2 is an exploratory 
arm to assess the preliminary effectiveness of the combination of NOX66 at the RP2D with 
ERBT in other solid tumors other than mCRPC. Up to a total of 15 patients are to be enrolled 
into Arm 2, comprising a mix of BC and NSCLC patients. For Part 2 of this study, once 25 
mCRPC patients have been enrolled into Arm 1, all additional recruitment into Arm 2 will 
also stop.  The sample sizes for Part 2 were selected to provide sufficient observations for the 
estimation of endpoints and to assess any signal of efficacy following NOX66 and EBRT 
treatment. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Full Analysis Set (FAS) 
The FAS comprises all patients who received at least one dose of 
study drug. 
Safety Analysis Set 
The Safety Analysis Set consists of all patients who received at 
least one dose of study drug.  In this study, the Safety Analysis 
Set will be the same as the FAS. 
This analysis set will be the primary analysis set for all safety 
endpoints. 
Per Protocol Set (PPS) 
The PPS consists of all patients in the FAS with ≥ 80% treatment 
compliance and without major protocol deviations. 
PK Analysis Set 
The PK analysis set consists of all patients in the Safety Analysis 
Set and who have at least one idronoxil or metabolite plasma 
concentration value. 


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Population (Analysis Set) 
Description 
Biomarker Analysis Set 
The Biomarker Analysis Set consists of all patients in the Safety 
Analysis Set and who have at least one plasma biomarker 
concentration value. 
Separate summaries may be provided for patients participating in Parts 1 and 2. 
9.4 Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized prior to database lock.  Below 
is a description of planned statistical analyses.  Further details are presented in the SAP. 
9.4.1 
General Considerations 
The main aims of the study are to assess the safety, tolerability, efficacy, PK and PD profiles of 
idronoxil (and selected metabolites) and EBRT in combination with NOX66 in patients with 
prostate cancer and other solid tumors. 
Concomitant medications, treatment exposure and study drug compliance will be summarized by 
dose cohort for Part 1 and by treatment arm for Part 2.  All summaries will be based on the 
Safety Analysis Set. 
Continuous data will be summarized using the number of patients (n), mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum.  Categorical data will be summarized 
using frequency tabulations (number and percentage of patients). 
Unless specified, no formal statistical hypothesis testing will be conducted and all analyses will 
be descriptive.  Two-sided 95% confidence intervals (CIs) will be presented alongside all point 
estimates to access precision. 
Baseline will be defined as the last measurement obtained prior to the first administration of 
NOX66. 
All statistical analysis will be performed using Statistical Analysis Software (SAS®) Version 9.3 
or higher. 
9.4.2 
Participant Disposition 
The disposition of all patients who sign an ICF will be provided.  The number of patients 
screened, enrolled, who received study drug, completed and discontinued will be summarized as 
well as the reason(s) for screening failure and all post-enrollment study or study drug 
discontinuations. 


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9.4.3 
Participant Demographics and Baseline Characteristics 
Participant demographics and baseline characteristics will be summarized separately for each 
study part using appropriate descriptive statistics.  Demographics and baseline characteristics 
will be summarized for Part 1 by dose cohort and will be based on the Full Analysis Set (FAS).  
For Part 2, demographics and baseline characteristics will be summarized by treatment arm and 
will be based on the FAS. 
Relevant medical history will be summarized in the same manner as described above. 
9.4.4 
Concomitant Medications 
Concomitant medications will be summarized separately for each study part.  All concomitant 
medications will be recorded in the eCRF and will be coded based on World Health Organization 
drug dictionary latest version.  Descriptive summaries will be provided by coded term. 
9.4.5 
Treatment Exposure and Study Drug Compliance 
Extent of exposure to NOX66 will include the following variables: 
• 
Total treatment duration (in weeks) = (date of last treatment – date of first treatment + 1)/7. 
• 
Relative Dose Intensity = 100 * (number of suppositories received/planned number of 
suppositories for duration of treatment). 
A record of the number of NOX66 suppositories dispensed to and taken by each patient will be 
documented.  The proportion of suppositories taken will be calculated and patients will be 
deemed compliant if this proportion is ≥ 80%. 
For EBRT, the date and time of each dose administered will be listed.  The site coordinator will 
confirm this information with the radiologist administering the EBRT and the date of 
administration will be added to the electronic data capture (EDC) system. 
9.4.6 
Primary Endpoint(s) 
9.4.6.1 
Part 1 (Dose Escalation): Recommended Phase 2 Dose 
The primary endpoint for Part 1 (dose escalation) is the number of DLTs, which will be used to 
estimate the MTD and select the RP2D.  This will be determined by the dose level at which no 
more than 1 patient out of 6 patients experiences a DLT during Cycle 1. 


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For assessment of DLTs, toxicities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) v22.0 or higher and graded according to NCI-CTCAE v5.0.  See 
Section 7.1.2.2 for details on DLT criteria. 
The number of DLTs experienced by a patient will be summarized by DLT type for each dose 
cohort and DLT events will be listed by patient.  The listing will include the description, severity 
and relationship of the events to study drug. 
9.4.6.2 
Part 2 (Dose Expansion) 
The primary endpoint for Part 2 (dose expansion) are: 
• 
Arm 1 (mCRPC): The proportion of patients who achieve ≥ 30% reduction in PSA from 
baseline at the end of Cycles 3 and 6. 
For patients with mCRPC, plasma levels of PSA will be collected on Day 1 of Cycles 1 to 5, 
every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at the EOT/ED Visit and at 12-weekly 
(±2 weeks) Follow-up Visits for all patients including those that discontinued for any reason 
other than disease progression, until the defined study end.  The number and proportions of 
patients with a ≥ 30% reduction in PSA levels from baseline to the end of Cycles 3 and 6 
(primary endpoint) and change from baseline at any time point (secondary endpoint) will be 
presented for Treatment Arm 1 along with the corresponding exact 95% CI (Clopper-Pearson). 
9.4.7 
Secondary Endpoint(s) 
9.4.7.1 
Safety of NOX66 and Both Doses of EBRT 
Safety profiles will be summarized by NOX66 dose cohort and separately by EBRT dose cohort 
(Part 1) or treatment arm and separately by EBRT dose cohort (Part 2) and will be based on the 
Safety Analysis Set. 
Adverse events will be coded using the MedDRA v22.0 or higher and will be graded according 
to the NCI-CTCAE v5.0.  Treatment-emergent AEs are defined as those AEs that either start or 
worsen in severity on or after the date of first administration of study drug and on or before 
30 days after the last dose of study drug. 
Treatment-emergent AEs will be summarized by severity grade and relationship to study drug.  
Serious AEs, serious TEAEs and TEAEs leading to discontinuation of study drug or to death will 
be presented. 


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Changes in clinical laboratory values, vital signs, ECGs and physical examinations will be 
summarized over time. 
9.4.7.2 
Efficacy of NOX66 
The following efficacy analysis will be conducted for the patients enrolled to Part 1 and Part 2 of 
the study.  All analyses are based on the FAS.  Results will be summarized by dose cohort 
(Part 1) or treatment arm (Part 2). 
For patients with mCRPC, the change in PSA from baseline will be summarized by dose cohort 
(Part 1) or treatment arm (Part 2, Arm 1) assessed using samples collected on Day 1 of Cycles 1 
to 5, every second cycle thereafter (i.e., Cycles 7, 9, 11 etc.), at 12-weekly (±2 weeks) follow-up 
visit until defined study end for all patients including those that discontinued for any reason other 
than disease progression.  A PSA response will be considered as a PSA value reduction ≥ 30% 
from baseline at the end of Cycles 3 and 6.  A PSA reduction from baseline at any time point will 
also be assessed as a secondary objective. This will be censored at the defined study end. 
Overall response rate, defined as the percentage of patients with CR and PR, will be assessed 
based on change from baseline imaging (RECIST v1.1 and PCWG-3 criteria for measurable or 
evaluable lesions).  The number and proportion of responders (CR and PR) will be presented 
along with the exact 95% CI (Clopper-Pearson) for the time points after Day 1.  Patients are 
allowed to continue study treatment until disease progression, unacceptable toxicity, withdrawal 
of consent, start of a new anticancer therapy, withdrawal of the patient by the Investigator or 
defined study end.   Tumor imaging assessment will be continued as scheduled for the patients 
who are discontinued from the study for reasons other than disease progression (see 
Section 8.1.3).  The best overall response (CR, PR, SD or progression) will be summarized. 
The change in ECOG from baseline will be summarized by dose cohort (Part 1) or treatment arm 
(Part 2) over time.  The change in pain severity and pain interference with daily activities from 
baseline will be summarized by dose cohort (Part 1) or treatment arm (Part 2) over time.  The 
number and proportion of patients with a pain response (≥ 2-point reduction in pain severity and 
no additional opioid use) will be summarized over time along with the exact 95% CIs 
(Clopper-Pearson).  The time to morphine administration and/or use of analgesics together with 
change from baseline assessment will be calculated and summarized by dose cohort (Part 1) and 
treatment arm (Part 2).  The number and proportion of patients with SREs and/or SSEs will be 
summarized at each time point and presented along with the exact 95% CI (Clopper-Pearson). 


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Quality of Life analyses will be performed for the Safety Analysis Set.  Scale measures from the 
EORTC-QLQ-C30, BPI-SF, PEQ, and FACT-P (mCRPC patients only) will be summarized for 
all patients by dose at each on-site visit as well as the change from baseline to each on-site visit. 
Survival functions will be computed for OS, PFS and PSA reduction/progression (for Part 2, 
Arm 1 only) using the Kaplan-Meier method.  Estimates of median survival times will be 
presented by dose cohort (Part 1) or treatment arm (Part 2) along with 2-sided 95% CIs.  The 25th 
and 75th percentiles and the range (minimum, maximum) will be presented as well. This will be 
censored at the defined study end. 
Duration of response is defined as the time from the first documented overall response of CR, PR 
or SD to the first documented overall response of progressive disease.  This will be estimated 
using the Kaplan-Meier method.  Estimates of median survival times will be presented along 
with the two-sided 95% CI.  The 25th and 75th percentiles and range (minimum, maximum) will 
also be presented. This will be censored at the defined study end. 
The effect of NOX66 on DCR as an Exploratory endpoint will be assessed based on the 
percentage of patients with the best overall response of CR or PR at any time plus SD from first 
dose administration until disease progression, death due to any cause or the start of new 
anticancer therapy, respectively.  This will be censored at the defined study end. RECIST v1.1 
criteria will be applied to assess CR, PR and SD.  Disease control rate will be presented for Part 
2, Treatment Arm 2 along with the corresponding exact 95% CI (Clopper-Pearson).  Tumor 
imaging and disease response assessments will be performed at 12-weekly (±2 weeks) follow-up 
visit after the last dose of study drug until disease progression, withdrawal of consent, initiation 
of new anticancer therapy, the patient is lost to follow-up, death, or until the defined study end, 
whichever comes first. DCR will be censored at the defined study end. 
9.4.7.3 
Pharmacokinetic Evaluation 
Plasma samples will be assayed for idronoxil and up to 7 selected metabolites by validated 
LC-MS/MS.  Individual plasma concentration-time data and plasma PK parameters will be 
summarized using descriptive statistics by treatment day and sampling time for idronoxil and the 
7 detectable metabolites (GIS/SIG, IG, GI, IS, SI, SIS, and GIG).  Plasma PK parameters will be 
determined by noncompartmental analysis for idronoxil and selected metabolites (SI, IS, GI, IG, 
SIG/GIS, GIG, SIS) and will be summarized by dose and treatment day. 
The following PK parameters will be estimated for idronoxil and the selected metabolites 
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Tmax, AUC(0-t), AUC(0-6), AUC(0-12), AUC(0-inf) and t½.  Details of the analyses will be included in 
the SAP. 
Dose proportionality will be assessed using the power model for Cmax, AUC(0-t), AUC(0-inf), 
AUC(0-6), and AUC(0-12) on Days 1, 6 and 14 of Cycle 1 for the parent compound. 
If data permits, accumulation ratios will be calculated for parent compound and selected 
metabolites for Cmax, Cmin, AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) for Days 6 and 14 of 
Cycle 1 (e.g., Day 14/Day 1 and Day 6/Day 1) and Day 8 of Cycles 2 and 3. 
The metabolite to parent ratios will be calculated (as data permit) for Days 1, 6 and 14 of 
Cycle 1, for AUC(0-t), AUC(0-inf), AUC(0-6), and AUC(0-12) and for single time points on Day 1 of 
Cycles 2 and 3. 
Concentration and PK parameter data will be listed, summarized and plotted.  Details of these 
analyses will be included in the SAP. 
There are no formal PK parameters for concentration data from Cycles 2 and 3 because these are 
single time points.  However, metabolite to parent ratios will be explored. 
Exploratory analyses of the relationship between plasma concentrations of parent drug and 
selected metabolites and/or PK parameters and AEs or PD biomarkers may be assessed by 
graphical methods and special summary tables.  Exposure-response relationship may also be 
explored. 
9.4.7.4 
Pharmacodynamic Biomarker Analysis 
Plasma levels of cytokines and chemokines will be evaluated as part of the PD analysis.  Using 
the plasma samples, analysis will be performed for ctDNA and lipidomic profiling. 
Absolute and change from baseline results of biomarker analysis will be summarized 
descriptively and also presented on a plot. 
9.5 Interim Analyses 
No formal interim analyses are planned. 
9.6 Data Monitoring Committee (DMC) 
A DMC will not be appointed.  Patient safety and scientific integrity of the study will be 
monitored by the SSC. 


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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
o Applicable International Conference for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. 
o Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC. 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, ICH 
GCP guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 


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10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary.  Patients will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, 
and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained.  The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient. 
 
Patients who are rescreened are required to sign a new ICF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB 
and signed by all patients subsequently enrolled in the study as well as those currently enrolled in 
the study. 
10.1.4 Data Protection 
Patients will be assigned a unique identifier by the Sponsor.  Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his personal study-related data will be used by the Sponsor in 
accordance with local data protection law.  The level of disclosure must also be explained to the 
patient who will be required to give consent for their data to be used as described in the informed 
consent. 
The patient must be informed that his medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members and by inspectors from regulatory authorities. 


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10.1.5 Committees Structure 
An SSC will be responsible for reviewing all safety data (see Section 7.1.2.1). 
10.1.6 Dissemination of Clinical Study Data 
All clinical study findings and documents will be regarded as confidential.  Study documents 
(protocol[s], IBs and other material) will be stored appropriately to ensure their confidentiality.  
The Investigator and members of his/her research team (including the IRB/IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the clinical study 
or to comply with regulatory requirements. 
The anonymity of participating patients must be maintained.  Patients will be specified on study 
documents (except patient identification Code List Log) by their patient number and year of 
birth, not by name.  The year of birth data will also be available to external study team members 
(e.g., collected on eCRF, central laboratory sample tubes and laboratory documents).  
Documents that identify the patient (e.g., the signed ICF) must be maintained in confidence by 
the Investigator. 
The clinical study may be considered for publication in the scientific literature irrespective of 
whether the results of the clinical study are positive or negative (Section 10.1.10).  In addition, 
the results of clinical studies will be provided on the publicly funded website 
www.ClinicalTrials.gov in line with the applicable regulations. 
10.1.7 Data Quality Assurance 
• 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data).  The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategies (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote or on-site monitoring) are provided in the Monitoring 
Plan. 


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• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CRO). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP and all applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator after study completion following local regulations or institutional 
policies.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party without 
written notification to the Sponsor. 
• 
All data generated by the site personnel will be captured electronically at each study center 
using eCRFs.  Data from external sources (such as laboratory data) will be imported into the 
database.  Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail.  The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
• 
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application.  The appropriate staff at the study site will answer queries sent 
to the Investigator.  The name of the staff member responding to the query and time and date 
stamp will be captured to provide an audit trail.  Once all source data verification is complete 
and all queries are closed, the monitor will freeze the eCRF page. 
• 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual.  In addition, site personnel 
will receive training on the EDC system/eCRF. 
10.1.7.1 Quality Assurance and Control 
The Sponsor is implementing and maintaining quality assurance (QA) and quality control (QC) 
systems with written SOPs to ensure that studies are conducted, and data are generated, 
documented, recorded and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s).  Where applicable, the QA and QC systems and written SOPs of the 
CRO will be applied. 


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The Sponsor or Sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities.  The audit may include on-site review of regulatory documents, eCRFs and source 
documents.  Direct access to these documents will be required by the auditors. 
10.1.8 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the Investigator’s site. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
Investigator may need to request previous medical records or transfer records, depending on the 
study.  Also, current medical records must be available. 
10.1.9 Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Sponsor may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of patients by the Investigator. 
• 
Discontinuation of further study drug development. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 


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regulatory requirements.  The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
10.1.10 Publication Policy 
• 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor at least 
30 days before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
• 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.  In this 
case, a coordinating Investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.11 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements.  The 
Sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  In addition, for the US, following above 
mentioned approval, the protocol amendment(s) will be submitted to the investigational new 
drug (IND) under which the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment.  All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.12 Liability and Insurance 
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements.  The insurance will cover any injury related to the study drug 
and clinical study experienced by the patient (if the patient followed all protocol procedures and 
restrictions).  The name and address of the relevant insurance company, the certificate of 
insurance, the policy number and the sum insured are provided in the Investigator’s Site File. 


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Details are provided in the ICF. 
10.1.12.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC/eCRF entries and individual patient’s medical records, assess study drug accountability and 
ensure that the study is being conducted according to pertinent regulatory requirements.  
EDC/eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. 
Checking of the EDC/eCRF entries for completeness and clarity and cross-checking with source 
documents, will be required to monitor the progress of the study.  Moreover, regulatory 
authorities of certain countries, IRBs, IECs and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections.  Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality.  The Investigator assures 
Parexel and the Sponsor of the necessary support at all times. 


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10.2 Appendix 2: Clinical Safety Laboratory Tests 
The tests detailed in Table 10-1 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Sections 5.1 
and 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 10-1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
BUN/Urea 
Creatinine 
Glucose (fasting or 
non-fasting) 
CO2/Bicarbonate 
Uric acid 
Potassium 
Sodium 
Calcium 
Chloride 
Magnesium 
Phosphate/ 
Phosphorus 
AST 
ALT 
ALP 
LDH 
GGT 
Total and direct 
bilirubin 
Albumin 
Total cholesterol 
Triglycerides 
 
 
Coagulation 
Prothrombin time, INR, aPTT 
Routine 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, urobilinogen, 
bilirubin, nitrite, WBCs, blood, creatinine (by dipstick) 
Microscopic examination (if blood or protein is abnormal) 
Serology 
HIV, HBsAg, anti-HBc and HCV antibody 
Baseline/Ongoing 
medical 
castration 
(mCRPC patients 
only) 
Testosterone levels 
COVID-19 
Testing (optional) 
SARS-CoV-2 RT-PCR2 


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Laboratory 
Assessments 
Parameters 
Pregnancy 
Testing 
Highly sensitive serum (Screening) and urine (other time points) human 
chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential)3 
NOTES: 
1 All events of ALT  3 × upper limit of normal (ULN) and bilirubin  2 × ULN (> 35% direct bilirubin) or ALT 
 3 × ULN and international normalized ratio (INR) > 1.5, if INR measured which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 To be assessed at Screening, each admission and may optionally be done at additional time points at the 
discretion of the Investigator. 
3 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; anti-HBc = hepatitis B core antibody; 
aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CO2 = carbon dioxide; GGT = gamma glutamyl transferase; HBsAg = hepatitis B surface antigen; HCV = hepatitis 
C virus; HIV = human immunodeficiency virus; IEC = Independent Ethics Committee; INR = international 
normalized ratio; IRB = Institutional Review Board; LDH = lactate dehydrogenase; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; RT-PCR = reverse transcription polymerase 
chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory coronavirus 2; ULN = upper 
limit of normal; WBC = white blood cell 
 
 


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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of a study drug, whether or not considered related to the 
study drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study drug. 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgement of the Investigator (e.g., not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study. 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses 
should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments.  
However, the signs, symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. 


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Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 
was at risk of death at the time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
intervention that would not have been appropriate in the physician’s office or outpatient 
setting.  Complications that occur during hospitalization are AE.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
• Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
• 
Medical or scientific judgement should be exercised in deciding whether SAE 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 medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive intervention 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. 


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10.3.3 Recording and Follow-up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) related to 
the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records 
to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor.  In this case, all patient identifiers, with the exception of the patient number, 
will be redacted on the copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study and classify it into one of Grade 1 through 5 using the NCI-CTCAE v5.0: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications and not bedridden. 


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An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as Grade 3 or higher. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgement to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy and other risk 
factors, as well as the temporal relationship of the event to study drug administration will 
be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor.  However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological examinations or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 


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• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAE  
For studies in the US: 
The Investigator must report any SAEs in the eCRF/EDC system within 24 hours of becoming 
aware of the event.  In the event the EDC system is down, the Investigator must complete the 
SAE form and provide the completed form to the Parexel Clinical Studies Safety Center using 
the email address provided to the sites on the eCRF/SAE form. 
When sending the completed SAE form via email, state that you are reporting an SAE and give 
the Investigator’s name, your name, the telephone number where you can be reached and the 
protocol number and title.  The event must be documented in the eCRF/EDC system when it is 
back online. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report 
and the Sponsor/Parexel will evaluate the seriousness and the causal relationship of the event to 
study drug.  In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the reference document (IB or Summary of Product Characteristics).  
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made 
concerning the need for further action. 
All SAEs will be recorded from signing of informed consent until 30 days after the last dose of 
study drug.  Serious adverse events occurring after the end of the study and coming to the 
attention of the Investigator must be reported only if they are considered (in the opinion of the 
Investigator) causally-related to study drug. 


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SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
Parexel International Corporation 
Clinical Studies Safety Center 
Medical Monitor 
Drug Safety Specialist 
(See SAE Reporting Instructions) 
 
1. Telephone the Medical Monitor using the number provided to sites to inform him/her 
that you have completed the SAE eCRF page/SAE form.  If the Medical Monitor is not 
available or you are calling after business hours (8:30 am to 5:30 pm Eastern time, 
Monday to Friday), leave a message in his/her voice mailbox. 
2. Provide the Medical Monitor with the Principal Investigator’s name, your name, the 
telephone number where you can be reached and the protocol number and title. 
3. Inform the Medical Monitor within 24 hours of becoming aware of the event and 
provide any supporting documentation to him/her within this time frame. 
4. After business hours, the Medical Monitor may be reached through Parexel’s 24-hour 
answering service on the number provided to the sites.  Give the answering service the 
protocol number, the study drug name and the Sponsoring pharmaceutical company. 
 
For Studies in the EU: 
All SAEs that occur during the study and all SAEs occurring up to 30 days after receiving the 
last dose of study drug, whether considered to be associated with the study drug or not, must be 
reported within 24 hours in the eCRF/EDC system.  If the EDC system is offline for any reason, 
the Investigator should complete the SAE form and provide the completed form to the Parexel 
Safety Contact using the email address provided to the sites. 
SAEs occurring after the end of the study should be reported to the Sponsor/Parexel by the 
Investigator if the Investigator considers there is a causal relationship with the study drug. 
The minimum information required for an initial report is (in situations where the EDC system is 
offline at time of reporting): 
• 
Name of person sending the report (e.g., name, address of Investigator). 
• 
Patient identification (Screening/participant number, initials, NOT patient name). 
• 
Protocol number. 


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• 
Description of SAE. 
• 
Causality assessment, if possible. 
However, as far as possible all points on the SAE form should be covered in the initial report or 
the completed SAE form itself must be emailed to the Parexel Safety Contact using the 
information provided to study sites.  The original SAE form must then be sent by mail to the 
Parexel Safety Contact.  In addition, the event must be documented in the eCRF/EDC system 
when it is back online. 
In case the Parexel Safety Contact cannot be contacted (e.g., out of normal working hours or at 
weekends), an automated reporting service is available.  The required information should be 
emailed, and a message should be left on the voicemail service (the relevant phone number/email 
address will be provided to all sites). 
After receipt of the initial report, the safety center will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event.  Parexel will 
be responsible for all information processing and reporting according to local legal requirements.  
Where necessary, Investigators will inform regulatory authorities in their own countries. 
For Studies in Australia: 
The Investigator must report any SAEs in the eCRF/EDC system within 24 hours of becoming 
aware of the event.  In the event the EDC system is down, the Investigator must complete the 
SAE form and provide the completed form to the Parexel Clinical Studies Safety Center using 
the email address provided to the sites on the eCRF/SAE form.  The original SAE form must be 
sent by mail to the Parexel Safety Contact and the event must be documented in the eCRF/EDC 
system when it is back online. 
All SAEs will be recorded from signing of informed consent until 30 days after the last dose of 
study drug.  Serious adverse events occurring after the end of the study should be reported to the 
Sponsor/Parexel by the Investigator if the Investigator considers there is a causal relationship 
with the study drug. 
The minimum information required for reporting of an SAE is (in situations where the EDC 
system is offline at the time of reporting): 
• 
Contact details of the person sending the report (e.g., name, address, phone number). 
• 
Patient identifier (e.g., Screening/participant number, initials, date of birth, but not their full 
name). 


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• 
Details of the product involved. 
• 
Protocol number. 
• 
Details of the suspected SAE (including causality and severity assessment). 
In case the Parexel Safety Contact cannot be contacted (e.g., out of normal working hours or at 
weekends), an automated reporting service is available.  The required information should be 
emailed, and a message should be left on the voicemail service (the relevant phone number/email 
address will be provided to all sites). 
After receipt of the initial report, the safety center/Sponsor will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event.  
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made 
concerning the need for further action.  Parexel will be responsible for all information processing 
and reporting according to local legal requirements.  Where necessary, Investigators will inform 
regulatory authorities in their own countries. 


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10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose administration, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
NOTE: Documentation can come from the site personnel’s review of the patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
o A high follicle-stimulating hormone (FSH) level in the post-menopausal range may 
be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  However, in the absence of 
12 months of amenorrhea, a single FSH measurement (> 40 IU/L) is required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 


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Contraception Guidance 
Male Patients: 
Male patients who have had a vasectomy may participate in this study provided that the absence 
of sperm has been confirmed.  If not, an additional highly effective method of contraception 
should be used.  Male patients with female partners of childbearing potential are eligible to 
participate if the agree to ONE of the following during the protocol-defined time frame in 
Section 5.1: 
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent. 
• 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
< 1% per year as described in the table below when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition, male patients must refrain from donating sperm for the duration of the study and for 
3 months after the last dose of study drug. 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female Patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below, and 
to not donate ova, for 3 months after the last dose of study drug. 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of < 1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 


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Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of < 1% per year when used consistently and correctly. 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation2 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If 
not, an additional highly effective method of contraception should be used. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for patients participating in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method.  In this case, two highly effective methods of contraception should be utilized during 
the treatment period and for at least 6 months after the last dose of study drug. 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
• 
Pregnancy testing will be performed according to the standard procedures of the study site. 
• 
Additional pregnancy testing should be performed during the treatment period (at the 
discretion of the Investigator).  During the Follow-up Visit period (up to 3 months after last 
dose of study drug), patients will be questioned about their pregnancy status and use of 
contraception. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 


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Collection of Pregnancy Information: 
Male Patients with Partners Who Become Pregnant 
• 
The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study.  This applies only to 
male patients who receive NOX66. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy.  The female 
partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to the Sponsor.  Generally, the follow-up 
will be no longer than 3 months following the estimated delivery date.  Any termination of 
the pregnancy will be reported regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
Female Patients Who Become Pregnant 
• 
The Investigator will collect pregnancy information on any female patients who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient’s pregnancy.  The 
patient will be followed to determine the outcome of the pregnancy.  The Investigator will 
collect any follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor.  Generally, follow-up will not be required for longer than 3 months 
beyond the estimated delivery date.  Any termination of the pregnancy will be reported, 
regardless of fetal state (presence or absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such.  Any post-study 
pregnancy-related SAE considered reasonably related to study drug by the Investigator will 
be reported to the Sponsor as described in Section 8.3.4.  While the Investigator is not 
obligated to actively seek this information in former study patients, he or she may learn of an 
SAE through spontaneous reporting. 
• 
Any female patient who becomes pregnant while participating in the study will discontinue 
study drug or will be withdrawn from the study. 
 
 


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10.5 Appendix 5: Tumor Imaging 
The revised RECIST guideline (version 1.1) will be used for assessment of tumor response in 
soft tissue lesions.  While either CT or MRI may be utilized, as per RECIST v1.1, CT is the 
preferred imaging technique in this study.6 
Bone lesions (mCRPC patients only) will be assessed using PCWG-37 criteria. 
 
 


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10.6 Appendix 6: European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire for Cancer Patients 
(EORTC-QLQ-C30) 
 


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10.7 Appendix 7: Brief Pain Inventory – Short Form 
 


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10.8 Appendix 8: Patient Experience Questionnaire (PEQ) 
 


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10.9 Appendix 9: Functional Assessment of Cancer Therapy – Prostate 
(FACT-P) Version 4 
 


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10.10 Appendix 10: Guidance for Low-Dose EBRT 
Simulation and Motion Management 
Simulation study using either CT or MRI +/- PET scans should be carried out as part of 
treatment planning.  The imaging will be performed to acquire the anatomy involved in the 
treatment with at least 5 cm of additional margin outside the planned radiation field to allow for 
adequate dose calculations.  The simulation scan will be used to identify the lesion(s) and 
surrounding normal critical organs to develop a treatment plan to deliver radiation in a manner 
that targets the lesion(s) accurately and spares critical organs as much as possible.  The 
simulation needs to account for tumor mobility and the scan techniques, where applicable, need 
to account for respiration, cardiac function, peristaltic activity, and organ filling and emptying. 
The utilization of 4D simulation technique will be at the treating physician discretion when 
treating 8 Gy in 1 fraction or 20 Gy in 4 fractions.  When treating with 25 Gy in 5 fractions, 4D 
simulation technique will be required in non-spinous lesions within 10 cm (either inferior or 
superior) of the diaphragm.  When 4D simulation technique is utilized multiple images will be 
acquired and regular points along the patients breathing cycle utilizing equipment and practices 
detailed by treatment site SOPs.  An internal gross tumor volume (iGTV) will be contoured to 
encompass the full range of tumor motion to be utilized for treatment planning purposes.  It will 
be up to the treating physician’s discretion to use techniques to reduce tumor motion and 
facilitate tumor tracking.  These techniques include breath-hold, abdominal compression, and 
fiducial marker placement.  
Guidelines described here will be superseded by any site-specific SOPs that require a higher 
degree of stringency. 
Immobilization 
Any immobilization equipment used must be fit for purpose.  When immobilizing the patient in 
preparation for treatment, it is necessary to ensure the patient is as comfortable as possible and is 
in a stable position.  This position needs to be reproducible at the time of treatment. 
Immobilization techniques must take into account the individual patient needs, organ motion and 
the complexity of the proposed radiation therapy technique.  Given treatment center variations in 
immobilization techniques, treatment-site SOPs will be followed regarding specific device 
utilization.  These devices include customized devices such as thermoplastic masks and 
vacuum-assisted immobilization devices (e.g., Vac-Lok), placement of radiopaque markers and 
marking tattoos, and non-custom devices such as wing board and MedTec devices. 


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Comprehensive documentation that itemizes patient immobilization methods and set-up details is 
required to ensure that the optimal treatment position is achieved and reproducibility errors are 
minimized. 
Treatment Planning and Verification 
• 
Dose prescribed will be 8 Gy in 1 fraction or 20/25 Gy in 5 fractions, aiming to cover at least 
99% of the PTV by 95% of the prescribed dose 
• 
No ‘hotspots’ within or outside of the PTV to exceed 110% of prescribed dose 
Treatment planning will include imaging procedures that will localize, delineate, and define 
target volumes and organs at risk, as well as enabling treatment verification.  This should be 
done according to the institutional SOP and allow both forward and inverse planning techniques 
where appropriate. 
Treatment planning needs to include: 
• 
Positioning and immobilization 
• 
Use of optimal imaging modalities 
• 
Delineation of treatment fields and isocenters 
• 
Measurements and patient contouring 
• 
Documentation 
• 
Patient consent to perform permanent skin marking procedures 
Treatment verification needs to match the simulated/planned treatment parameter with that set on 
the treatment unit.  The position of the treatment isocenters, radiation treatment field and/or its 
shape or anatomical volume must be evaluated against that determined in the treatment planning 
process. 
The EBRT to be administered in the context of this study is for symptomatic relief and pain 
management, and not for the purpose of ablative therapy.  As such, the prescribed EBRT should 
only be given to target lesions and normal tissues should be spared.  If 25 Gy in 5 fractions is 
prescribed, it will be encouraged but not required that daily kV or MV imaging is obtained with 
every fraction and that on-board axial imaging is obtained on the first day of treatment. 
For 25 Gy in 5 fractions, images must be obtained for image guidance prior to each fraction to 
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Normal Tissue Constraints  
In the context of this study, it is a requirement that the radiation oncologist will follow the 
QUANTEC Guidelines for normal tissue constraints when administering low-dose EBRT (20 Gy 
in 5 fractions or 8 Gy in 1 fraction) to metastatic lesions7.  For 25 Gy in 5 fractions, the dosing 
guidance from the AAPM Task Force Group 101 has to be followed2.  This study will be 
excluding all patients who have central nervous system involvement; therefore, the CNS tissue 
tolerances, with the exception of spinal cord exposure, will not be included in the guidance on 
normal tissue dose constraints as set out below.  These constraints are for EBRT at low dose and 
for standard fractionation. 
Tissue / Organ 
Tissue radiation dose constraints 
(maximum radiation dose) 
Spinal cord 
23 Gy 
Retina 
< 50 Gy 
Cochlea 
≤ 45 Gy 
Single parotid gland sparing 
< 20 Gy 
Irradiation to 2 parotid glands 
< 25 Gy (spread across 2 glands) 
Mandible 
≤ 70 Gy 
Pharyngeal constrictors 
< 50 Gy 
Larynx 
< 44 Gy 
Brachial plexus 
< 60 Gy 
Lung 
20 Gy 
Oesophagus 
< 34 Gy 
Heart 
< 26 Gy 
Liver 
≤ 28 Gy 
Kidney 
< 18 Gy per kidney 
Stomach 
< 50Gy 
Small bowel (irradiation to less than one-
third) 
50 Gy 
Rectum 
< 27 Gy 
Skin 
40 Gy 
Bladder 
< 65 Gy 
Femoral head 
< 52 Gy 
 


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Equipment 
Radiation delivery equipment needs to have undergone appropriate dosimetry calibration using 
an acceptable phantom to ensure that the correct treatment beam energies are being generated, 
correct alignment between on-board imaging and treatment isocenter, and accurate motion of the 
treatment couch.  This calibration needs to be performed at a minimum of once every 3-4 years 
to ensure acceptable quality control as per treatment site SOPs. 
Treatment Dose Interruptions 
Treatment dose interruption for the single fraction Gy regimen is not applicable. 
For a patient who will be receiving 20/25 Gy over 5 fractions, dose interruption must occur if a 
patient experiences a Grade 3 or higher adverse reaction in any organ/tissue that is due to the 
radiation therapy.  The fractionated therapy can only resume once the adverse reaction has 
recovered or stabilized back to Grade 2 or less. 
Patients with tumors involving the central nervous system are excluded from this study.  It is 
anticipated that over 50% of patients recruited into this study will require symptomatic low-dose 
EBRT to bony metastases, with involvement of other soft tissue organ lesions for the rest of the 
patients. 
References 
1. Radiation Oncology Practice Standards Part B: Guidelines.  The Royal Australian and 
New Zealand College of Radiologists – Faculty of Radiation Oncologists. 
2. Benedict SH et al.  Stereotactic body radiation therapy: The report of the AAPM Task 
Group 101.  Med Phys.  37(3): August 2010. 
3. RTOG/EORTC Late Radiation Morbidity Scoring System.  http://wwwrtog.org/Research 
Associates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchem
a.aspx 
4. de Ruysscher D et al.  European Organisation for Research and Treatment of Cancer 
(EORTC) recommendations for planning and delivery of high-dose, high precision 
radiotherapy for lung cancer.  Radiotherapy and Oncology.  124 (2017): 1-10. 
5. Boehmer D et al.  Guidelines for primary radiotherapy of patients with prostate cancer. 
Radiotherapy and Oncology.  79 (2006): 259-269. 
6. Emami B. Tolerance of Normal tissue to Therapeutic Radiation.  Reports of Radiotherapy 
and Oncology. Vol. 1No. 1. Spring 2013. 


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7. Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC). Int. J. 
Radiation Oncology Biol. Phys., Vol. 76, No. 3 Supplement, pp. S1-S160. 2010 


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10.11 Appendix 11: Country-Specific Requirements 
<To be adjusted per country requirements> 
 
 


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10.12 Appendix 12: Abbreviations and Trademarks 
ADL 
Activities of daily life 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
Akt 
Antiapoptotic kinase B 
ALT 
Alanine aminotransferase 
Anti-HBc 
Hepatitis B core antibody 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC(0-6) 
AUC from time zero (predose) to 6 hours postdose 
AUC(0-12) 
AUC from time zero (predose) to 12 hours postdose 
AUC(0-inf) 
AUC from time zero (predose) extrapolated to infinity 
AUC(0-t) 
AUC from time zero (predose) to time of last quantifiable concentration 
BC 
Breast cancer 
BID 
Twice daily 
BP 
Blood pressure 
BPI-SF 
Brief Pain Inventory – Short Form 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
COVID-19 
Coronavirus disease 2019 
CO2 
Carbon dioxide 
CR 
Complete response 
CRO 
Clinical Research Organization 
CT 
Computerized tomography 
ctDNA 
Circulatory tumor deoxyribonucleic acid 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
EBRT 
External beam radiotherapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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eCRF 
Electronic case report form 
ED 
Early Discontinuation 
EDC 
Electronic data capture 
ENOX 
Ecto-NOX disulfide-thiol exchanger 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire for Cancer Patients 
EOT 
End of Treatment 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
Gy 
Gray 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LuPSMA-617 
177lutetium prostate-specific membrane antigen 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
n 
Number of patients/events 


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NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NCSLC 
Non-small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PCWG-3 
Prostate Cancer Working Group 3 
PD 
Pharmacodynamic(s) 
PEQ 
Patient Experience Questionnaire 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PI3 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic(s) 
PPS 
Per protocol Set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PSA 
Prostate-specific antigen 
PSMA 
Prostate-specific membrane antigen 
QA 
Quality assurance 
QC 
Quality control 
QoL 
Quality of life 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
RT-PCR 
Reverse transcription polymerase chain reaction 
S1P 
Sphingosine-1-phosphate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis Software 
SD 
Stable disease 
SoA 
Schedule of Activities 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SRE 
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SSC 
Safety Steering Committee 
SSE 
Symptomatic skeletal events 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal phase half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to first occurrence of Cmax 
TMEP 
Transmembrane electron potential 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
 
 
 


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11 References 
1. Crumbaker M, Pathmanandavel S, Yam AO, Nguyen A, Ho B, Chan L, et al.  Phase I/II 
Trials of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and 
Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer 
(LuPIN).  European Association of Urology 2020 (accessed 17 Sep 2020).  Available online 
at: https://doi.org/10.1016/j.euo.2020.07.002. 
2. Investigator’s Brochure – NOX66.  Noxopharm Limited.  Edition 8.0, 11 Feb 2021. 
3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.  Global Cancer Statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 
185 countries.  CA Cancer J Clin. 2018;68(6):394-424. 
4. Pathmanandavel S, Crumbaker M, On Wah Yam A, Rofe C, Ho B, Ling Chan W, et al. Final 
results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of 
combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic 
castration-resistant prostate cancer (LuPIN trial). [Poster] Exhibited at: 2021 Genitourinary 
Cancers Symposium. Available at: https://meetinglibrary.asco.org/record/194976/abstract 
5. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP.  
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group.  Am J Clin 
Oncol. 1982;5(6):649-655. 
6. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation criteria 
in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
7. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the 
Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. 
 
 


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Investigator Agreement Page 
Declaration of the Principal or Global Coordinating Investigator 
<This page should be used for studies with EU sites but is not mandatory for US studies.> 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
This study protocol (Version 4.0, dated 23 Nov 2022) was subjected to critical review and has 
been approved by the Sponsor.  The information it contains is consistent with the current 
risk/benefit evaluation of the study drug as well as with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki, as amended in 
1996 and the guidelines on Good Clinical Practice. 
Principal or Global Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 


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Declaration of the National Coordinating Investigator <country-specific, please adjust as 
required> 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
This study protocol (Version 4.0, dated 23 Nov 2022) was subjected to critical review and has 
been approved by the Sponsor.  The information it contains is consistent with the current 
risk/benefit evaluation of the study drug as well as with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki, as amended in 
1996 and the guidelines on Good Clinical Practice. 
National Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 


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Declaration of the Investigator 
Title: A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients 
with Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol (Version 4.0, dated 23 Nov 2022), Investigator's Brochure, EDC system/electronic CRF 
(eCRF) and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC.  No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature  
  
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number