Clinical trial NCT05100628
Conditions: Metastatic Soft-tissue Sarcoma
Keywords: Doxorubicin Dose-escalation study Dose-expansion study Maximum tolerated dose
Sponsor: Noxopharm Limited
Start date: 2022-02-11; Completion date: 2023-05-26
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase I, open-label, dose-escalation and dose-expansion study of NOX66 given rectally, in cohorts of patients with metastatic soft tissue sarcoma (STS) who have not been exposed to anthracycline therapy, using a fixed dose-escalation schema every 21 days to establish the maximum tolerated dose (MTD) of the combination of NOX66 and doxorubicin.

Detailed description:
The study will contain dose-escalation cohorts and dose-expansion cohorts. The study design allows an exploration of different doses of NOX66 with safety monitoring to ensure the safety of the patients.

Dose-escalation cohorts: It will include three planned Treatment Groups (800, 1200, 1800 mg daily) and patients enrolled in these groups will receive 7 days of monotherapy treatment with NOX66 followed by a 5-day washout period. Thereafter, patients will enter a combination therapy (only if no significant toxicity is observed during monotherapy). This will commence with Cycle 1, which will consist of 7 days of NOX66, and on Day 2 of the 21-day cycle, doxorubicin will be administered. Patients will continue to be treated for up to 6 x 21-day cycles of NOX66 and doxorubicin. New patients will be entered at the next dose level of NOX66, if no dose-limiting toxicities have occurred among the first 3 patients at the end of cycle 1. During the dose-escalation, MTD of the combination of NOX66 and doxorubicin will be determined.

Dose-expansion cohort: On completion of the dose-escalation cohort, patients will be enrolled into a dose-expansion at the MTD of the combination of NOX66 and doxorubicin. All patients will enter directly into 21-day combination cycles and will be given NOX66 therapy for 7 days and doxorubicin will be administered on Day 2 of each cycle. Treatment will be terminated upon disease progression, unacceptable toxicity, or a maximum of 6 cycles.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: NOX66 intervention 2: NOX66 intervention 3: NOX66 intervention 4: NOX66 intervention 5: Doxorubicin
Intervention descriptions: intervention 1: NOX66 800 mg (400 mg suppository twice daily \[BID\]).

Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles. intervention 2: NOX66 1200 mg daily (600 mg suppository BID).

Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles. intervention 3: NOX66 1800 mg daily (600 mg suppository thrice daily).

Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles. intervention 4: MTD of the combination of NOX66 and doxorubicin will be determined in the dose-escalation cohort of the study. The selected dose will be administered in combination with Doxorubicin. intervention 5: Doxorubicin will be given at 75 mg/m\^2 as an intravenous infusion on Day 2 of the 21-day cycle for up to 6 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
NOXOPHARM LIMITED 
 
CONFIDENTIAL 
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Version 4.0, 21 March 2022 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
A dose escalation and dose expansion study of NOX66 plus 
doxorubicin in anthracycline-naïve, adult patients with soft tissue 
sarcoma - CEP-2 
Protocol Number: 
NOX66-004 
Product: 
 
Idronoxil suppository (NOX66) 
Sponsor: 
 
Noxopharm Limited 
Level 20, Tower A, The Zenith 
821 Pacific Highway 
Chatswood NSW 2067  
Australia  
Telephone: +61 2 9144 2223 
Fax: + 61 2 9199 9600 
 
 
  
 
 
Version: 
            4.0 
 
 
 
 
Date:  
            21 March 2022  
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you for the exclusive use as an 
Investigator or consultant for review by you, you staff, and the applicable Institutional Review Board 
(IRB), and is subject to recall at any time. Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written authorization 
from Noxopharm Ltd. These restrictions on disclosure apply to all future oral or written information 
supplied to you that is designated as ‘Privileged’ or ‘Confidential’. 


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


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1  PROTOCOL SYNOPSIS 
Name of 
Company 
Sponsor 
Noxopharm Limited Suite 3, 828 Pacific Highway, Gordon, NSW 2072 
(‘Noxopharm’), and incorporating its various subsidiary companies. (ABN 50 608 
966 123) 
Title of Study 
A dose escalation and dose expansion study of NOX66 plus doxorubicin in 
anthracycline-naïve, adult patients with soft tissue sarcoma – CEP-2 
Study Number 
NOX66-004 
IND Number 
TBD 
Study Identifier 
and Registry 
ClinicalTrials.gov Identifier: NCT05100628 
Development 
Phase 
Phase I 
Name of Active 
Ingredient  
Idronoxil 
Description of 
Investigational 
Product 
Idronoxil (NOX66) is a multiple signal transduction regulator which results in cell 
death 
via 
extrinsic 
and 
intrinsic 
apoptosis, 
anti‐angiogenesis, 
and 
immunomodulation via stimulation of natural killer cell activity. The study drug 
is formulated in a single use suppository with a proprietary lipophilic base 
containing 400 or 600 mg of idronoxil.   
Indication 
Anthracycline naïve adult patients with metastatic soft tissue sarcoma for whom 
treatment with doxorubicin is considered to be appropriate.  
Study 
Objectives 
Primary objectives:  
• 
To estimate the maximum tolerated dose (MTD) of NOX66 in combination 
with doxorubicin 
• 
To characterize the safety and tolerability of NOX66 alone and in 
combination with doxorubicin.  
Secondary objectives: 
• 
To determine single and multiple dose pharmacokinetics (PK) of idronoxil  
• 
To determine the preliminary efficacy and quality of life (QOL) of the MTD 
of NOX66 in combination with doxorubicin. 
 
Exploratory objectives: 
• 
To investigate the relationship between response to NOX66 plus 
doxorubicin and the following: 
a. Dose of NOX66 
b. Histopathology (if prior tissue samples/slides are available) 
c. Genetic mutations 
d. Change in lipid profile from baseline 
e. Cytokine/chemokine and Ecto-NOX disulfide-thiol exchanger 2 
(ENOX2) dynamics   
f. Acceptability of NOX66 dosage form 
 


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Study Design: 
This is a Phase I, open-label, study of NOX66, given rectally in cohorts of 
patients with metastatic soft tissue sarcoma who have not been exposed to 
anthracycline therapy, using a fixed dose-escalation schema every 21 days 
to establish the MTD. In previous clinical trials, NOX66 has been 
administered to 18 cancer patients from 400 to 800 mg daily for 14 days 
prior to combination with carboplatin. In another study 25 patients received 
up to 16 days of 400 to 1200 mg/day while undergoing radiotherapy. Overall, 
NOX66 has been well tolerated. 
Dose-Escalation 
For all dose escalation cohorts, there will be 7 days of monotherapy 
treatment with NOX66 followed by a 5- day washout period prior to the start 
of combination cycles of NOX66 and doxorubicin. The purpose of the 
monotherapy treatment is to evaluate the safety and tolerability of NOX66 
when administered alone and as well as single and multiple dose PK of 
idronoxil.  
The study will include three planned Treatment Groups (800, 1200, and 1800 
mg daily) of 3 patients each. The first 3 patients will be entered at Dose Level 
1 and will be given NOX66 (800 mg daily dose for 7 days) which will be 
followed by a washout period of 5 days.  On Day 1 patients will be monitored 
for cardiac effects with 12-lead electrocardiograms (ECG) over 8 hours and 
PK samples will be collected for 24 hours. Patients will be closely monitored 
for any AEs during monotherapy. If no significant toxicities (defined below) 
are observed after 7 days of monotherapy and following a 5-day rest period, 
patients will enter combination therapy. This will commence with Cycle 1, 
which will consist of 7 days of NOX66 at 800 mg/day and on Day 2 of the 21-
day cycle, doxorubicin will be administered at approximately 1 hour after 
application of NOX66. After a rest period of 2 weeks, Cycle 2 will be initiated 
with another 7 days of NOX66 treatment at the same dose (800 mg/day) and 
another dose of doxorubicin on Day 2. Patients will continue to be treated 
for up to 6 x 21-day cycles of NOX66 and doxorubicin in the same manner.  
Three new patients will be entered at the next dose level of NOX66, if no 
dose-limiting toxicities (DLTs) have occurred at the end of Cycle 1.  
In all cohorts, doxorubicin will be given initially at 75 mg/m2 as an 
intravenous infusion over 15 minutes (or as per standard of care). This dose 
may be reduced to 60 mg/m2, at the Investigator’s discretion for 
unacceptable Grade >2 toxicity. Lower doses of doxorubicin (50% or 75% 
reduction) will be used of If serum bilirubin is 1.2 -3.0 mg/dL or 3.1 – 5.0 
mg/dL prior to a cycle, respectively.  
Assessment of MTD 
At any given dose level, if 1 of 3 patients develops a DLT during Cycle 1, then 
dose escalation will halt temporarily, and an additional 3 patients will be 
enrolled at the same dose level. If no further DLTs occur, then dose 
escalation will resume.  
If 2 or more patients at a given dose level experience DLTs during Cycle 1, 
dose escalation will be halted, and that level will be declared the DLT dose 


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level. The previous dose level will then be considered for expansion to 6 
patients in order to confirm that it is the MTD level. The MTD is defined as 
the dose level at which no more than 1 patient out of 6 experienced a DLT 
up to the end of Cycle 1. If in the first group at 800 mg daily (Cohort 1), 2 or 
3 patients develop DLTs, then that dose level is considered to be the DLT 
level and 3 additional patients need not be tested at that level, but lower 
doses should be studied.    
If no DLT is observed at 1800 mg (Cohort 3), dose escalation will be stopped. 
The proposed highest dose level (1800 mg) will be declared the MTD, and 
additional patients will be enrolled, if necessary, to ensure that a total of 6 
patients are evaluated at this dose level.  
The dose escalation scheme is presented in the following table. 
Proposed Starting Dose and Dose Escalation Scheme for NOX66 
Cohort 
1 
2 
3 
Increment 
 NA 
50% 
50% 
Total daily dose (mg) 
800   
1200 
1800   
Daily regimen (mg) 
400 BID 
600 BID 
600 TID 
 BID = twice daily, TID = three times daily. For each cohort, safety/tolerability 
and PK data will be collected on Days 1-2 and 7-8 for respective doses.  
Assessment of toxicities and decisions about dose escalation and cohort 
expansion will be made by a Safety Review Committee, that will include at 
least one Sponsor representative participating investigators, and may also 
include a cardiologist or other outside consultants at the Sponsor’s 
discretion.  
Assessment of DLTs 
Patients who withdraw in Cycle 1 for reasons other than safety or toxicity 
will be replaced. During the 7-day Monotherapy Period, any patient who 
develops a significant toxicity, as noted below, will be replaced. 
For determination of DLT during Cycle 1, toxicity will be graded using the 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Version 5.0. Any of the following, if judged to be associated with 
NOX66 alone or in combination with doxorubicin (i.e., possibly-, probably-, 
or definitely related to), will be considered a DLT: 
1) Grade 3 non-hematological toxicities (excluding alopecia) with the 
following exceptions:  
i. Grade 3 nausea/vomiting or diarrhea <72 hours with adequate 
antiemetic and other supportive care 
ii. Grade 3 fatigue <1 week 
iii. Grade 3 electrolyte abnormality that lasts 24 to 72 hours 
(Investigator’s discretion for timeframe), is not clinically complicated 


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and resolves spontaneously or responds to conventional medical 
interventions. 
2) Grade 4 non-hematologic (non-laboratory) toxicity of any duration  
3) Grade 3 or Grade 4 febrile neutropenia of any duration not caused by 
doxorubicin. It is well known that a dose-dependent, reversible 
leukopenia and/or neutropenia are the predominant manifestations 
of doxorubicin hematologic toxicity and are the most common acute 
dose-limiting toxicities of this drug. With the recommended dose 
schedule, leukopenia is usually transient, reaching its nadir 10 to 14 
days after treatment with recovery usually occurring by the 21st day.  
4) Grade 3 thrombocytopenia in combination with a Grade 3 or greater 
blood and lymphatic system disorder, not attributable to doxorubicin 
5) Grade 3 AST or ALT that is associated with a Grade 2 or greater rise 
in bilirubin 
Growth factor support can be administered during combination cycles, 
except during Cycle 1 in the Dose Escalation Cohorts. The recommended 
Phase 2 dose (RP2D) may be defined as the highest dose administered at 
which no more than 1 patient (out of 6) experiences a DLT and the dosage 
form, including the dosing frequency, is acceptable to patients.  
Cohort Expansion 
After the Dose Escalation Part is completed, 16 patients will be enrolled into 
a Dose Expansion Cohort at the MTD of the combination of NOX66 and 
doxorubicin. All patients will enter directly into 21-day combination cycles 
and will be given NOX66 therapy for 7 days and doxorubicin will be 
administered on Day 2 (1 hour after the morning dose of NOX66 dose is 
administered). This will be followed by a 2-week rest period. Treatments will 
continue up to 6 cycles.  
Treatment will be terminated upon disease progression, unacceptable 
toxicity or a maximum of 6 cycles. In patients who develop Grade 3 or 4 
toxicity determined to be related to NOX66, the Investigator may reduce the 
dose or frequency of dosing by one level so that the patients can remain in 
the study. All patients will be actively followed up for about 14 months 
following completion of Cycle 6 (including scheduled visits every 3 months) 
followed by telephone follow-up / chart review, for progression free survival 
(PFS) and overall survival (OS), at 15 and 18 months following completion of 
Cycle 6. 
Pharmacokinetics 
During the Monotherapy phase, on Day 1 blood samples will be collected for 
PK analysis of idronoxil at pre-dose (within 15 minutes prior to dosing) and at 
1, 2, 3, 4, 6, and 8 hours post application. On Day 2, a pre-dose sample will be 
collected prior to application of NOX66. This sample can be collected in the 
clinic or at the patient’s home. Exact times for dosing and blood sampling will 
be recorded. If a bowel movement occurs, during the collection period, the 
time of each bowel movement should be recorded, and the collections should 
continue as planned. Blood plasma will be analysed for the quantification of 


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idronoxil and metabolites using a validated liquid chromatography-tandem 
mass spectrometry method.   
On Day 7 of the NOX66 monotherapy period blood samples will be collected 
in the clinic for PK analysis of idronoxil at pre-dose (within 15 minutes prior 
to dosing) and at 1, 2, 3, 4, 6, and 8 hours post application after the morning 
dose. The remainder of the daily dose will be administered at 8 (TID regimen) 
or 12 (BID regimen) hours after the first morning dose of NOX66. On Day 8, 
the last PK sample will be obtained at 8 or 12 hours after the last dose of 
monotherapy on Day 7. The samples obtained on the first day of the washout 
period (Day 8) can be collected in the clinic or at the patient’s home. The 
exact time the samples are collected must be recorded. 
Cycle 1: On Day 2, PK samples are to be collected prior to and at 1 and 2 hours 
post NOX66 administration and assayed for idronoxil and metabolites. PK 
samples are to be collected at 0.5, 4, and 6 hours after the end of the 
doxorubicin infusion and assayed for doxorubicin and doxorubicinol. On Day 
7, PK samples will be obtained just prior to the morning dose of NOX66 and 
on Day 8 at 8 or 12 hours after the last dose on Day 7 for the TID and BID 
regimens, respectively. The exact times of dosing and collection of the blood 
samples for PK analysis after administration of NOX66 and doxorubicin must 
be recorded. 
Cycles 2, 4 and 6: On Day 2 PK samples are to be collected prior to 
administration of NOX66 and assayed for idronoxil and metabolites. On 
Day 2, PK samples are to be collected at 0.5 and 4 hours post doxorubicin 
infusion (note: 0.5-hour post-dose doxorubicin PK sample is not applicable at 
Cycle 4). The 0.5-hour sample will be assayed for doxorubicin and 
doxorubicinol and the 4-hour sample will be assayed for idronoxil and 
metabolites, doxorubicin, and doxorubicinol. 
Cycles 3 and 5: On Day 2, PK samples are to be collected 4 hours after the 
morning dose of NOX66 and just prior to the morning dose on Day 7 and on 
Day 8 at 8 or 12 hours after the last dose on Day 7 for TID and BID regimens, 
respectively. 
In the Dose Expansion Cohort, PK samples are to be obtained on Day 2 of 
Cycle 1 prior to morning dose of NOX66 and prior to the last morning dose of 
NOX66 on Day 7. PK samples for doxorubicin are to be collected at 0.5, 4 and 
6 hours after the end of doxorubicin infusion. The 0.5-hour sample will be 
assayed for doxorubicin and doxorubicinol and the 4- and 6-hour samples will 
be assayed for idronoxil and metabolites, doxorubicin and doxorubicinol. On 
Day 2 of Cycles 2, 4 and 6, PK samples for doxorubicin are to be collected at 
0.5 and 4 hours after the end of doxorubicin infusion and PK samples are to 
be collected prior to and at 4 hours post NOX66 and assayed for idronoxil and 
metabolites. On Day 2 of Cycles 3 and 5, PK samples are to be collected at 4 
hours after the morning dose of NOX66 and just prior to the morning dose on 
Day 7 and assayed for idronoxil and metabolites. 
 
 


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Cardiac Monitoring  
Day 1 Monotherapy: Triplicate 12-lead ECGs will be obtained after 5 minutes 
of rest in the supine position at -0.75, -0.5 and -0.25 hours prior to 
administration of NOX66 and at 1, 2, 5, and 8 hours after the first dose of 
NOX66 monotherapy. Additional ECGs in triplicate may be taken more 
frequently if QTc intervals exceed 500 ms during the study. The ECG 
parameters, QT, QT interval adjusted for the patient’s heart rate by 
Fridericia’s method (QTcF), PR, QRS, and RR intervals; heart rate; and T-wave 
amplitude, as well as any change from baseline, will be assessed and the 
relationship between NOX66 blood concentrations may be explored to 
determine if there is an effect on QTcF.  
Day 7 Monotherapy: Triplicate 12-lead ECGs will be obtained after 5 minutes 
of rest in the supine position at -0.75, -0.5 and -0.25 hours prior to 
administration of NOX66 and at 1, 2, 5, and 8 hours after the morning dose 
of NOX66. Holter monitoring will be used to record cardiac activity from 8 to 
24 hours after the last morning dose of NOX66 monotherapy in each cohort.  
Cycle 1 Day 2: Triplicate 12-lead ECGs will be obtained after 5 minutes of rest 
in the supine position at -0.75, -0.5 and -0.25 hours prior to administration of 
NOX66 and at 1, 2, 5, and 8 hours after the morning dose of NOX66. Cardiac 
activity will be recorded with Holter monitoring from 8 to 24 hours after 
administration of NOX66.  
Cycles 2 to 6 Day 2 (combination of NOX66 and doxorubicin): Triplicate 12-
lead ECGs will be obtained after 5 minutes of rest in the supine position at 
- 0.25 hours prior to and at 1, 2, 5, and 8 hours post application of NOX66. 
Months 6, 9 and 12: Triplicate 12-lead ECGs will be obtained after 5 minutes 
of rest in the supine position. 
Echocardiography will be conducted at Screening, Day 1 of Cycles 3 and 5, 
and at the end of Cycle 6 or Early Termination (if the patient discontinues 
prior to 6 cycles).  
Radiological Imaging  
Tumor imaging (CT/MRI) for determination of response rate and PFS during 
the study, will be performed at Screening (if scans are not done within 28 
days of registration and Cycle 1 Day 1), prior to the start of Cycles 1 (only in 
the Dose Escalation Cohorts if the baseline scan was done more than 28 days 
from C1D1), at the end of Cycles 2, 4 and 6, at 6, 9 and 12 months after the 
start of the combination therapy and at the End of Study or at Early 
Termination (ET) if the patient discontinues from the trial.  
Safety Assessments 
Adverse events (AEs) will be monitored by the Investigator during the study. 
Other safety assessments will include physical examination, vital signs, 
12- lead ECGs (including Holter recordings), hematology, clinical chemistry, 
and urinalysis laboratory tests, as well as brain type natriuretic peptide (BNP) 
and troponin I assessments. 


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Study Period and 
Duration of 
Treatment 
Screening will take up to 28 days prior to the first dose of NOX66. The study 
duration from initial administration of NOX66 to the last follow up is 
approximately 20 months including Screening. The lead-in NOX66 
monotherapy period is 12 days, then 6 x 21-day cycles of NOX66 + 
doxorubicin, followed by 14 months of active follow up (including scheduled 
visits and telephone follow-up / chart review for PFS and OS). 
Study Sites and 
Location  
Approximately 12 sites in the United States and Australia 
Patient Eligibility 
Criteria: 
Inclusion Criteria 
Patients must satisfy all of the following criteria to be included in the study: 
1. Adult patients (≥18years of age, inclusive at the time of signing the 
informed consent) with histologically confirmed diagnosis of metastatic 
or recurrent soft tissue sarcoma. 
2. Patients for whom treatment with doxorubicin is considered to be 
appropriate (haemoglobin >10 g/dL, ANC >1000/μL3, and platelets 
> 100,000/μL3), serum bilirubin < 1x the institutional upper limit of 
normal (ULN) (unless known Gilbert’s disease), AST or ALT < 3x 
institutional ULN, and creatinine clearance ≥50 mL/min as assessed by 
the Cockcroft-Gault equation. 
3. Left ventricular ejection fraction ≥50%. 
4. Disease that is considered measurable according to RECIST v1.1. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 
6. Anticipated life-expectancy of at least 6 months. 
7. For females of reproductive potential the following are considered highly 
effective acceptable forms of contraception: surgical sterilization (tubal 
ligation); total abstinence from sexual intercourse with the opposite sex; 
established hormonal birth control (e.g., oral, transdermal, injection, or 
implant) plus a barrier method or a double barrier method (intrauterine 
device, spermicide, or diaphragm plus condom) for at least 1 month prior 
to screening and agreement to use such a method during study 
participation and for an additional month after the last dose of NOX66 or 
6 months after the last dose of doxorubicin, whichever is longer. 
8. For males of reproductive potential: vasectomy or use of highly effective 
contraception (e.g., condoms, abstinence) during the study and until 3 or 
6 months after the last dose of NOX66 or doxorubicin, respectively, 
whichever is longer. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be disqualified from 
entering the study: 
1. Histologically or cytologically confirmed Kaposi’s sarcoma, 
gastrointestinal stromal tumor (GIST), extra-skeletal myxoid 
chondrosarcoma, epithelioid hemangioendothelioma, and desmoid 
tumor.  


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2. Hepatic impairment defined as serum bilirubin > 1 x ULN (unless known 
Gilbert’s disease) or either AST or ALT > 3x institutional upper limit of 
normal. 
3. Unstable angina pectoris, angioplasty, cardiac stenting, or myocardial 
infarction 6 months before study entry. 
4. Untreated metastases to the CNS. 
5. Received previous treatment with anthracyclines and anthracenediones. 
6. Previous radiation therapy to the mediastinal or pericardial area. 
7. A known allergy to any of the treatment components. 
8. Active or chronic infection with human immunodeficiency virus (HIV). 
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. Pregnant (positive urine pregnancy test) or lactating. 
10. Patient not willing to use suppositories. 
11. Patients with a colostomy.  
12. Patients who have had a colectomy (total or left hemicolectomy) with re-
anastomosis. 
13. Patients for whom administration of the suppositories are likely to cause 
pain (e.g., inflamed hemorrhoids, fissures, or lesions of the anus or 
rectum). 
14. Patients with fecal impaction, chronic idiopathic constipation, or chronic 
diarrhea or alternating irritable bowel disease. 
15. Patients with inflammatory bowel disease (e.g. Crohn’s disease or 
ulcerative colitis). 
16. Previous treatment with an investigational agent or the non-approved 
use of a drug or device within 4 weeks before study entry  
17. Uncontrolled diabetes mellitus. 
18. Patients who require concomitant use of strong inhibitors or inducers of 
CYP3A4, CYP2D6 or P-glycoprotein (P-gp). 
Dosage Form, 
Dose, and Route of 
Administration: 
Idronoxil will be provided in 400 mg and 600 mg strength suppositories, for 
BID or TID rectal administration by trial participants. 
Doxorubicin provided as 10 mg, 20 mg, 50 mg or 200 mg powder for injection 
to be administered as an intravenous infusion, over 15 minutes (or as per 
standard of care), every 21 days at the recommended dose of 75 mg/m2. In 
addition, the Investigator may use dexrazoxane to reduce the incidence and 
severity of cardiomyopathy associated with the use of doxorubicin. However, 
the degree of myelosuppression may be increased at Cycles 5 and 6 with the 
use of dexrazoxane. Doxorubicin should be given within 15 minutes after 
beginning the infusion with dexrazoxane. [Note: For breast cancer patients, 
dexrazoxane is recommended when doxorubicin cumulative dosage is ≥ 
300 mg/m2]. 
Criteria for 
Evaluation 
 
 
 
The following criteria will be used to evaluate the safety of NOX66 alone and 
in combination with doxorubicin: 
• 
24-hour Holter/ monitoring  
• 
12-lead ECGs (in-patient) 
• 
Serum transaminases, bilirubin 
• 
BNP and troponin I 
• 
Echocardiography 


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• 
Complete blood count 
• 
Electrolytes (Ca++, Mg++), PO4, BUN, creatinine  
The following criteria will be used to evaluate the efficacy of NOX66 alone 
and in combination with doxorubicin: 
• 
RECIST v1.1: Disease Control Rate (DCR) defined as [(stable disease (SD)+ 
partial response (PR) + complete response (CR)/All)], overall response 
rate (ORR) 
• 
Overall survival (OS), Progression Free Survival (PFS) 
• 
European Organization for Research and Treatment of Cancer: Core 
Quality of Life Questionnaire v3.0 (EORTC QLQ-C30) 
• 
Fatigue Severity Scale (European Organisation for Research and 
Treatment of Cancer: Cancer Related Fatigue Module - EORTC QLQ-FA12) 
• 
Brief Pain Inventory (short form) 
• 
Suppository Acceptance Questionnaire  
The following criteria will be used to evaluate the PK of idronoxil and 
metabolites in blood plasma after single and repeated doses of NOX66: 
• 
Maximum concentration (Cmax)  
• 
Time to reach maximum concentration (Tmax)  
• 
Trough concentrations after repeated administration 
• 
Area under the concentration-time curve up to last measurable time 
point and infinity (AUClast and AUCinf)  
• 
Area under the concentration-time curve over a dosing interval after 
repeated administration (AUCτ)  
• 
Terminal elimination half-life (if possible) 
 
Pharmacokinetic parameters of idronoxil and metabolites obtained on Day 7 
will be compared to Day 1 values. Sparse PK sampling for determination of 
idronoxil and metabolites, doxorubicin and doxorubicinol concentrations will 
be obtained during the treatment cycles to assess variability of exposure of 
idronoxil and doxorubicin in an exploratory manner.  
 
The following biomarkers will be evaluated to assess the relationship 
between response to NOX66 and doxorubicin: 
• 
Genetic mutations 
• 
Change in lipid profile from baseline 
• 
Cytokine/chemokine and ENOX2 dynamics  
Number of 
Patients (Planned)  
Up to approximately 34 patients with metastatic soft tissue sarcoma will be 
studied if the MTD is determined with the maximum dose planned for this 
study. If a minimum number of patients is studied per dose escalation, the 
expected number of patients is approximately 28.  
Statistical 
Methods 
Sample size: 
Up to 18 patients may be enrolled in the Dose Escalation part of this study, in 
cohorts of 3 or 6 patients at each specified dose. Sixteen patients will be 
enrolled in the Cohort Expansion part of this study. Patients must take at least 
80% of their prescribed doses to be considered eligible for MTD evaluation. 
These sample sizes will be adequate to provide a safety profile for dose 
selection and to describe the PK characteristics of idronoxil. If patients are 


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replaced in the Monotherapy period, in Cycle 1 or 2, the number of patients 
will be higher than 34. 
Analysis sets: 
There will be two analysis sets 
• 
Safety Set: All patients treated with at least one dose of idronoxil will be 
included in the Safety Set (SS). All analyses of safety, toxicity, and PK will 
be performed for this set. 
• 
Full Analysis Set (FAS): All patients who completed at least one cycle of 
combination therapy (at any NOX66 dose). 
Analyses of efficacy, tolerability, and biomarkers will be performed for the 
FAS.  Separate summaries may be provided for patients participating in the 
Dose Escalation and Dose Expansion parts. 
Safety (Primary analysis): 
The safety profile will be based on Serious Adverse Events (SAEs), Treatment 
Emergent Adverse Events (TEAEs), standard clinical laboratory parameters 
(clinical chemistry, hematology, urinalysis), vital signs measurements, ECG 
parameters, and physical examination findings. 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory 
Activities and summarized by dose when NOX66 is given alone or in 
combination with doxorubicin. The number and percentage of patients 
reporting TEAEs will be calculated overall, by system organ class, and by 
preferred term for each dose level. Adverse events will also be graded for 
severity according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0.   
Serious Adverse Events (SAEs) will be summarized separately.   
Cardiac AEs (including clinically significant abnormalities in ECG rhythm and 
waveform morphology reported as TEAEs) and changes in echocardiographic 
parameters will be summarized. 
Descriptive statistics will be provided for demographics, baseline 
characteristics, and exposure to treatment by cohort.   
Univariate summary statistics will be provided by dose group at each visit for 
quantitative laboratory parameters and vital signs and for the change from 
baseline in these parameters. For laboratory values and vital signs with 
defined CTC grades, shift tables will be provided for CTC grades from baseline 
to end of study and from baseline to worst value on study.   
Univariate summary statistics will be presented for ECG parameters for the 
value at each measurement time point and the change from baseline to each 
measurement time point. A similar analysis will be provided for the worst 
value of each ECG parameter on study. 
Findings from physical examinations and ECOG performance status will be 
summarized by dose of NOX66 given alone or in combination with 
doxorubicin. 
 
Pharmacokinetics (Secondary analysis): 
Individual blood concentration-time data and blood PK parameters will be 
summarized using descriptive statistics by dose and sampling time for 
idronoxil and metabolites. Separate summaries will be provided for PK 


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samples collected for single-dose administration, repeated administration, 
and administration in combination with doxorubicin. 
Blood PK parameters will be determined by noncompartmental analysis for 
idronoxil and metabolites and will be summarized by dose and treatment 
day. Concentrations of idronoxil obtained in the presence of doxorubicin will 
be compared to monotherapy.   
Concentrations of doxorubicin and doxorubicinol will be determined after the 
administration of the infusion in the presence of NOX66 and will be compared 
to historical controls. 
The relationship between PK parameters and AEs and other safety findings 
may be assessed by graphical methods and special summary tables. 
 
Efficacy (Secondary analysis): 
The DCR, ORR, and the incidences of CR, PR, SD, and Progressive Disease (PD) 
as assessed by RECIST v1.1 criteria will be summarized for the MTD of the 
combination by counts and percentages and exact 95% confidence intervals 
at the end of Cycles 2, 4, and 6, at the 6-month, 9-month, and 12-month 
follow-up visits and at End of Study. 
Survival functions will be computed for OS and PFS by the Kaplan-Meier 
method. Estimates of median OS and median PFS will be presented.  
 
Quality of Life (Secondary Analysis): 
Quality of Life analyses will be performed for the FAS. Scale measures from 
the EORTC QLQ will be presented by dose for each visit, along with change 
from baseline to each visit. Brief pain inventory items and fatigue parameters 
will be summarized by dose at each visit as well as the change from baseline 
to each visit. 
 
Exploratory Analysis: 
An exploratory analysis will be performed to assess various factors which may 
contribute to response to the combination of NOX66 and doxorubicin. These 
factors include, NOX66 dose or exposure, cytokine, chemokine and ENOX2 
response, lipidomic profiling (capturing over 300 lipid species as determined 
by liquid chromatography-tandem mass spectrometry), histopathology, and 
specific genetic mutations. The acceptability of the suppository dosage form 
by patients will also be determined. 
 
Interim Analysis: 
An interim analysis will be performed after all patients in the Dose Escalation 
part of the study have either discontinued or completed 3 treatment cycles, 
whichever comes first. A second interim analysis may also be performed after 
50% of the patients in the expansion cohort have either discontinued or 
completed 3 treatment cycles.  
The results from these analyses will not be used to modify the design of this 
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TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ......................................................................................................... 3 
2 
LIST OF TABLES ................................................................................................................. 19 
3 
LIST OF FIGURES ............................................................................................................... 19 
4 
LIST OF ABBREVIATIONS .................................................................................................. 20 
5 
ROLES AND RESPONSIBILITIES ......................................................................................... 22 
5.1 
SPONSOR ............................................................................................................... 22 
5.2 
INVESTIGATOR AND SITES ..................................................................................... 22 
5.3 
KEY NOXOPHARM PERSONNEL.............................................................................. 22 
5.4 
OVERSIGHT COMMITTEE ....................................................................................... 22 
6 
INTRODUCTION ................................................................................................................ 22 
6.1 
BACKGROUND AND RATIONALE ............................................................................ 22 
6.2 
CHOICE OF COMPARATOR OR CONTROL .............................................................. 25 
7 
STUDY OBJECTIVES ........................................................................................................... 26 
7.1 
PRIMARY OBJECTIVEs ............................................................................................ 26 
7.2 
SECONDARY OBJECTIVES ....................................................................................... 26 
7.3 
EXPLORATORY OBJECTIVES ................................................................................... 26 
8 
STUDY DESIGN AND OVERALL INVESTIGATIONAL PLAN.................................................. 26 
8.1 
OVERALL INVESTIGATIONAL PLAN ........................................................................ 26 
8.1.1 
Dose-Escalation .................................................................................................. 26 
8.1.2 
Cohort Expansion ............................................................................................... 28 
8.2 
STUDY TREATMENTS ............................................................................................. 28 
8.3 
DEFINITION AND DETERMINATION OF MTD AND DLT .......................................... 28 
8.3.1 
Definition of MTD .............................................................................................. 28 
8.3.2 
Determination of MTD ....................................................................................... 28 
8.3.3 
Definition of DLT ................................................................................................ 29 
8.3.4 
Determination of DLT......................................................................................... 30 
8.3.5 
Evaluable Patient ............................................................................................... 30 
8.3.6 
Patient Replacement.......................................................................................... 30 
9 
STUDY PARTICIPANTS ...................................................................................................... 30 


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9.1 
STUDY POPULATION .............................................................................................. 30 
9.2 
INCLUSION CRITERIA.............................................................................................. 31 
9.3 
EXCLUSION CRITERIA ............................................................................................. 31 
9.4 
STUDY WITHDRAWAL CRITERIA ............................................................................ 32 
9.5 
TREATMENT WITHDRAWAL CRITERIA ................................................................... 32 
10 STUDY MATERIALS ........................................................................................................... 33 
10.1 
STUDY PRODUCT.................................................................................................... 33 
10.1.1 Investigational Product Formulation and Description ....................................... 33 
10.1.2 Investigational Product Presentation, Storage and Handling............................ 33 
10.1.3 Investigational Product Labelling ....................................................................... 33 
10.1.4 DOXORUBICIN, GROWTH FACTORS, DEXRAZOXANE ......................................... 33 
10.2 
INVESTIGATIONAl PRODUCT ADMINISTRATION ................................................... 34 
10.2.1 Administration ................................................................................................... 34 
10.2.2 Duration of therapy ........................................................................................... 34 
10.2.3 Dose Modifications ............................................................................................ 35 
10.3 
ACCOUNTABILITY FOR CLINICAL SUPPLIES ............................................................ 36 
10.4 
CONCOMITTANT THERAPIES ................................................................................. 36 
11 STUDY PROCEDURES AND FLOW CHART ......................................................................... 37 
11.1 
OUTCOME MEASURES ........................................................................................... 37 
11.1.1 Primary Endpoints .............................................................................................. 37 
11.1.2 Secondary Endpoints ......................................................................................... 37 
11.2 
RECRUITMENT ....................................................................................................... 39 
11.2.1 Method Assigning Subjects to Treatment Groups ............................................. 39 
11.2.2 Treatment Discontinuation ................................................................................ 40 
11.3 
STUDY PROCEDURES .............................................................................................. 40 
11.4 
CLINICAL ASSESSMENTS ........................................................................................ 42 
11.4.1 Demographic and Other Baseline Characteristics ............................................. 42 
11.4.2 Safety ................................................................................................................. 42 
11.4.3 Pharmacokinetics ............................................................................................... 46 
11.4.4 Efficacy ............................................................................................................... 48 


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11.4.5 Pharmcodynamics .............................................................................................. 49 
11.5 
ASSESSMENT OF DISEASE STATUS ......................................................................... 49 
11.5.1 Radiologic ........................................................................................................... 49 
11.5.2 Treatment Response .......................................................................................... 49 
11.6 
STUDY VISITS .......................................................................................................... 49 
11.6.1 Screening (Days -28 to -1) .................................................................................. 49 
11.6.2 Treatment Period ............................................................................................... 50 
12 METHODS OF ASSIGNMENT OF INTERVENTION.............................................................. 65 
12.1 
ALLOCATION OF TREATMENT ................................................................................ 65 
12.2 
BLINDING AND UNBLINDING ................................................................................. 65 
13 DATA COLLECTION AND MANAGEMENT ......................................................................... 65 
13.1 
METHODS .............................................................................................................. 65 
13.1.1 Electronic Case Report Form ............................................................................. 66 
13.1.2 Storage of Documents ....................................................................................... 66 
13.2 
DATA MANAGEMENT ............................................................................................ 66 
13.2.1 Data Coding ........................................................................................................ 66 
13.2.2 Data Validation .................................................................................................. 66 
14 STATISTICAL SECTION....................................................................................................... 67 
14.1 
SAMPLE SIZE .......................................................................................................... 67 
14.2 
ANALYSIS SETS ....................................................................................................... 67 
14.3 
STATISTICAL METHODOLOGY ................................................................................ 67 
14.3.1 General Statistics Methods ................................................................................ 67 
14.3.2 Disposition, Demographics, and Baseline Disease Condition ............................ 68 
14.3.3 Exposure to Treatment ...................................................................................... 68 
14.3.4 Adverse Events ................................................................................................... 68 
14.3.5 Laboratory summaries ....................................................................................... 69 
14.3.6 Vital signs ........................................................................................................... 69 
14.3.7 ECG parameters ................................................................................................. 69 
14.3.8 Other Safety Analyses ........................................................................................ 69 
14.3.9 Pharmacokinetic Analyses ................................................................................. 70 


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14.3.10 
Efficacy Analyses ............................................................................................ 70 
14.3.11 
Quality of Life ................................................................................................. 71 
14.3.12 
Statistical Analysis Plan .................................................................................. 71 
14.4 
INTERIM AND ADDITIONAL ANALYSIS ................................................................... 71 
15 MONITORING ................................................................................................................... 71 
15.1 
MONITORING OF CASE REPORT FORMS ............................................................... 71 
15.2 
SAFETY DATA MONITORING .................................................................................. 71 
15.2.1 Safety Monitoring and Oversight ....................................................................... 72 
15.2.2 Safety Reviews ................................................................................................... 72 
15.3 
AUDITING ............................................................................................................... 73 
16 ADVERSE EVENT REPORTING ........................................................................................... 74 
16.1 
DEFINITIONS .......................................................................................................... 74 
16.1.1 Adverse Events ................................................................................................... 74 
16.1.2 Serious Adverse Events ...................................................................................... 75 
16.1.3 Guidelines for determining Causality and Severity ........................................... 76 
16.1.4 Action Taken and Outcome ............................................................................... 77 
16.2 
RESPONSIBILITIES FOR REPORTING ....................................................................... 77 
16.2.1 SAE and Unresolved AE Follow-Up .................................................................... 78 
16.2.2 Investigator Reporting of AEs/SAEs/Deaths after Study Discontinuation ......... 78 
16.2.3 Sponsor SAE Reporting Requirements ............................................................... 78 
17 CONDUCT OF STUDY ........................................................................................................ 79 
17.1 
HUMAN RESEARCH ................................................................................................ 79 
17.2 
SUBJECT CONFIDENTIALITY ................................................................................... 79 
17.3 
REGULATORY APPROVAL ....................................................................................... 79 
17.4 
GOOD CLINICAL PRACTICE ..................................................................................... 80 
17.5 
ADHERENCE TO PROTOCOL ................................................................................... 81 
17.5.1 Protocol Violation and Reporting ...................................................................... 81 
17.6 
SUPPLY OF NEW INFORMATION AFFECTING THE CONDUCT OF THE STUDY ....... 82 
17.7 
PROTOCOL AMENDMENTS .................................................................................... 82 
18 SUBJECT INFORMED CONSENT ........................................................................................ 83 


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19 DISCLOSURE OF DATA ...................................................................................................... 83 
19.1 
CONFIDENTIAL INFORMATION .............................................................................. 83 
19.1.1 Study Records and Source Documents .............................................................. 84 
19.1.2 Prior to Study Commencement ......................................................................... 84 
19.1.3 Document Retention .......................................................................................... 84 
19.1.4 Access to Source Documents ............................................................................. 85 
19.2 
PUBLICATION POLICY ............................................................................................. 85 
20 ADDITIONAL SUBJECT CARE DURING POST-STUDY ......................................................... 86 
20.1 
EMERGENCY CONTACT .......................................................................................... 86 
20.1.1 Investigator ........................................................................................................ 86 
20.1.2 Sponsor .............................................................................................................. 86 
20.2 
LIABILITY AND INSURANCE .................................................................................... 86 
21 REFERENCES ..................................................................................................................... 87 
22 APPENDICES ..................................................................................................................... 89 
22.1 
CONSENT................................................................................................................ 89 
22.2 
SPECIMEN COLLECTION ......................................................................................... 89 
22.2.1 Clinical Laboratory Tests .................................................................................... 89 
22.2.2 PharmacoKinetic, PharmacoDynamic Samples and electrocardiographic 
timepoints ........................................................................................................................ 89 
22.2.3 Genetic Mutations and histopatholgy ............................................................... 91 
22.2.4 Chemokines, cytokines AND ENOX2 .................................................................. 91 
22.3 
INHIBITORS AND INDUCERS OF CYTOCHROME P450 ENZYMES ........................... 93 
INHIBITORS ....................................................................................................................... 94 
INDUCERS ......................................................................................................................... 96 
 
 
 
 
 
 
 


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2 LIST OF TABLES 
Table 1 
 Proposed Starting Dose and Dose Escalation Scheme for NOX66 ....................... 34 
Table 2  
Treatment Periods ................................................................................................. 41 
Table 3 
 Clinical Laboratory Assessments .......................................................................... 45 
Table 4 
 Schedule of Procedures and Assessments for Three Periods of the Study .......... 59 
Table 5 
 Relationship to Study Drug ................................................................................... 76 
Table 6 
 Adverse Event Outcome Category ........................................................................ 77 
Table 7 
 Pharmacokinetic Sampling Times for NOX66 and Doxorubicin ........................... 89 
Table 8 
 ECG Timepoints ..................................................................................................... 91 
Table 9 
 Pharmacodynamic Sampling time Points ............................................................. 92 
Table 10 
Inhibitors and Inducers of Cytochrome P450 Enzymes ......................................... 93 
 
3 LIST OF FIGURES 
Figure 1 
Study Schematic .................................................................................................... 42 
 
 
 


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4 LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC inf  
Area under the concentration-time curve up to infinity 
AUClast 
Area under the concentration-time curve up to the last measurable time 
point 
AUCτ  
Area under the concentration-time curve over a dosing interval 
BID 
Twice daily 
BNP 
Brain type natriuretic peptide 
Cmax  
Maximum observed blood concentration 
CRO 
Contract research organization 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events   
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid  
ECOG 
Eastern Cooperative Oncology Group  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ENOX2 
Ecto-NOX disulfide-thiol exchanger 2 
EORTC 
European Organization for Research and Treatment of Cancer 
ET 
Early termination 
GCP 
Good Clinical Practice  
HEENT 
Head, ears, eyes, nose, throat 
HR 
Hazard ratio  
HIV 
Human immunodeficiency virus 
IC50 
Inhibitory concentration of 50%  
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 


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ABBREVIATION 
DEFINITION 
IRB 
Institutional review board 
Kel 
Terminal elimination rate constant 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
ORR 
Objective response rate 
OS 
Overall survival  
P-gp 
P glycoprotein 
PFS 
Progression free survival  
PK 
Pharmacokinetics 
PD 
Progressive disease 
PR 
Partial response 
QD 
Once daily 
QOL 
Quality of life 
QRS 
QRS interval on electrocardiogram 
QTc 
QT interval corrected for heart rate  
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAQ 
Suppository Acceptance Questionnaire 
SD 
Stable disease 
SRC 
Safety review committee 
STS 
Soft tissue sarcomas  
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
T1/2 
Terminal elimination phase half-life 
Tmax  
Time to reach maximum concentration 
 


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5 ROLES AND RESPONSIBILITIES 
5.1 SPONSOR 
Noxopharm Limited (Noxopharm) is responsible for the study design, data collection and 
management, analysis and interpretation of data, writing of the Clinical Study Report (CSR), 
and publication of the study results. The study is funded by Noxopharm.  
Noxopharm reserves the right to terminate the study at any time. A written explanation will 
be provided to the Investigator should the study be terminated. Each Investigator is 
responsible to inform the Institutional Review Board (IRB) of such a decision and to return all 
study materials to the Sponsor. The Sponsor will also update the status of the study in the 
Annual Report to FDA. 
5.2 INVESTIGATOR AND SITES 
The primary roles and responsibilities of all Investigators and other study personnel at all sites 
are to recruit the appropriate patients for this study, monitor the safety of all the patients 
and follow the protocol. This study will be conducted in the US and Australia and will take 
place in academic hospitals or treatment centers.  
The sites and Investigators will be paid for their time and use of facilities. There are no 
conflicts of interest. 
5.3 KEY NOXOPHARM PERSONNEL 
Individuals and their roles from Noxopharm are shown below. 
Function 
Name 
Affiliation 
Chief Medical Officer 
Dr Gisela Mautner 
Noxopharm 
Medical Monitor 
Dr Marissa Lim 
Noxopharm 
5.4 OVERSIGHT COMMITTEE  
The Safety Review Committee, (SRC) will include at least one sponsor representative, 
participating Investigators and may also include a cardiologist or other outside consultants 
at the Sponsor’s discretion. The primary role of the SRC is to assess toxicities, if needed, to 
determine if they meet the definition of a dose-limiting toxicity (DLT) and make decisions 
about dose escalation and what dose will be used in the cohort expansion.  
6 INTRODUCTION 
6.1 BACKGROUND AND RATIONALE 
Soft tissue sarcomas (STSs) are mesenchymal neoplasms that can arise from any site within 
the body, including the extremity, trunk, retroperitoneum, and head and neck. These are 
biologically heterogeneous diseases, with over 50 subtypes that vary by molecular, 
histological, and clinical characteristics. The most common subtypes of high-grade STS include 


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undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, and 
malignant peripheral nerve sheath tumors. Collectively, STSs are rare, accounting for <1% of 
adult cancers, with an estimated 12,310 new cases in 2016 in the United States (1). 
Unfortunately, up to 50% of high-risk patients with high-grade STS develop metastases and 
die from their disease (2). Among the young adult and pediatric population under 20 years of 
age, STS is one of the top five causes of cancer-related death (1). The median overall survival 
(OS) for advanced, metastatic STS has historically been in the range of 12 months, while more 
recent randomized studies have noted survival approximating 18–19 months (3-10). 
Nonetheless, improvements in the management of high-grade STS are needed.  
Anthracyclines (e.g. doxorubicin) remain the standard of care for first-line therapy in 
high- grade STS, regardless of subtype, presentation and patient characteristics. 
Anthracyclines intercalate into deoxyribonucleic acid (DNA), thereby blocking DNA and 
ribonucleic acid synthesis, while also interfering with topoisomerase II, leading to DNA 
breakage.  Doxorubicin has single-agent activity in high grade STS, and demonstrates a dose–
response relationship, with doses lower than 60 mg/m2 associated with inferior efficacy (11, 
12). Because of its toxicity profile however, most dose-intensive treatment schedules 
administer doxorubicin at 75 mg/m2 for otherwise fit patients (13, 14).  
In a large multicenter 455-patient study, doxorubicin (75 mg/m2) in combination with an 
alkylating agent (e.g. ifosfamide), given alone every 3 weeks over 6 cycles showed a higher 
response rate (RR), 26.5% compared with doxorubicin alone 13.6% (p < 0.0006). The 
combination also significantly improved progression free survival (PFS) from 4.6 months to 
7.4 months [hazard ratio (HR) 0.74, p = 0.003], but there was no significant difference 
between the two treatments in OS (14.3 months versus 12.8 months, HR 0.83, p = 0.076).  
Despite its efficacy, there was higher toxicity when using the combination, with 18% of 
patients receiving doxorubicin plus ifosfamide and 3% of patients receiving doxorubicin alone 
being unable to complete the planned 6 cycles of therapy due to adverse events (AEs). It 
should be noted the most common Grade 3–4 toxicities when administering doxorubicin and 
ifosfamide are related to bone marrow suppression which highlights the need for regular 
blood-count monitoring, supportive transfusions and growth factor support (14, 15, 16).  
These findings suggest that combination chemotherapy provides better outcomes for tumor 
shrinkage, but improvement in OS is lacking, although part of the problem may be overlapping 
toxicities in the regimens that have been studied. 
In a combined Phase 1b/2 study (n=15/133), olaratumab, a platelet-derived growth factor 
receptor-α blocking antibody in combination with doxorubicin was evaluated for the 
treatment of anthracycline-naïve STS (17). Patients were treated for up to 8 cycles with the 
combination doxorubicin and olaratumab and longer with olaratumab alone. Although the 
median PFS was not significantly improved with olaratumab at 6.6 months compared with 4.1 
months for doxorubicin alone, the median OS was 26.5 months with olaratumab, compared 
with 14.7 months in the doxorubicin alone arm. This almost 1-year difference in OS indicates 


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that another agent with a different mechanism of action and toxicity profile from doxorubicin 
may provide improved outcomes in STS, compared to doxorubicin alone. 
Idronoxil, a small molecule, acts by binding Ecto-NOX disulfide-thiol exchanger 2 (ENOX2) – a 
tumor-specific form of external membrane NADH oxidase. As such, the activity of idronoxil is 
highly specific to tumor cells. Binding of idronoxil to ENOX2 leads to a disruption of the 
sphingomyelin 
pathway, 
preventing 
the 
conversion 
of 
ceramide 
to 
sphingomyelin- 1- phosphate (S1P), and subsequently a cascade of events leading to 
apoptosis. In vitro idronoxil potently sensitizes a broad range of cancer cell lines and adds to 
the cytotoxic effects of standard chemotherapeutic agents from various classes. In addition, 
it has been demonstrated that Idronoxil reverses pre-existing resistance (e.g. sensitizes 
platinum-resistant cells to carboplatin) (18, 19, 20). 
In other studies, optimal sensitization with idronoxil occurred with a 24-hour period of 
idronoxil pre-treatment followed by a 120-hour treatment with a chemotoxin. Several clinical 
trials have been conducted with idronoxil using intravenous and oral routes of administration. 
The addition of oral idronoxil [(400 mg three times daily (TID)] to platin based therapy 
provided no clinical benefit in patients with platinum-resistant ovarian cancer, but there was 
some evidence of activity in small cell sarcoma or adenocarcinoma of the cervix, vagina or 
vulva. The high rate of metabolism of oral idronoxil may have led to the failure to show clinical 
activity in these studies. 
To circumvent the high rate of metabolism, a rectal formulation was developed, and one 
Phase 1 study has been completed in 18 patients with solid tumors. Idronoxil suppository was 
administered [400 mg once daily (QD) or 400 mg twice daily (BID)] for 14 consecutive days 
followed by 7 days off treatment. After completion of the NOX66 monotherapy period, 
carboplatin was added on Day 2 of 7 consecutive days of NOX66 treatment in each cycle. The 
combination phase of the study consisted of 3 cycles of NOX66 and low-dose carboplatin 
(AUC=4) followed by three cycles of NOX66 and a higher dose of carboplatin (AUC=6). The 
patients who completed the monotherapy and all cycles, received NOX66 for a maximum of 
56 days and carboplatin for up to 6 cycles. The most common treatment-emergent adverse 
event (TEAE) by System Organ Class was blood and lymphatic system disorders, with 44% of 
the patients, half of which experienced mild to severe anemia. In terms of tumor response, 
at Cycle 6, 1 patient had a partial response (PR), and most had stable disease (SD). Of the 3 
deaths in the study, 2 were due to progressive disease and one may have been related to the 
combination of NOX66 and carboplatin, although an autopsy was not performed. 
An ongoing Phase 1 study is evaluating the combination of NOX66 plus palliative doses of 
radiotherapy (RT) in patients with metastatic castrate resistant prostate cancer who have 
failed all available treatment. In the first part of the study (dose escalation), 14 patients were 
treated with either 400, 800 or 1200 mg/day NOX666 (n=4-6/dose) for up to 16 days. 
Radiotherapy was administered over 8 days and NOX66 treatment began on the day prior to 
RT and continued until 7 days following completion of RT. In the second part of the study a 
dose expansion cohort (n=12) with 1200 mg NOX66 is underway. 


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In 25 patients studied to date, mild (Grade 1) TEAEs of fatigue have been attributed to both 
NOX66 and radiation, while occurrences of mild dry mouth, oral mucositis, and stomatitis 
have been considered related to NOX66 alone. Cases of mild radiation dermatitis, 
oropharyngeal pain, and moderate anaemia and urinary tract infection have been considered 
related to RT alone. 
Three patients in the 800 mg dose cohort died due to disease progression, ≥30 days after the 
last NOX66 dose. Two of these patients experienced severe (Grade 3) TEAEs. One patient 
developed lymphopenia, and hypocalcemia immediately after completion of treatment, 
followed one month later by nausea, vomiting, and subsequent death. The other patient 
developed anaemia after completion of treatment and hypophosphatemia 20 days post 
treatment completion both of which resolved. Almost three (2.75) months later the patient 
died. One patient in the 1200 mg dose cohort died due to disease progression ≥30 days after 
the last NOX66 dose. None of these deaths were considered related to NOX66.  
The majority of all other TEAEs were mild to moderate (Grades 1-2). Other Grade 3 TEAEs 
were asthenia, back pain or bone pain, which were reported in 3 patients.  
The present study will assess the safety, tolerability, and pharmacokinetics (PK) of NOX66 
using a wider range of doses than were tested in the first Phase 1 studies as well a different 
cytotoxic agent. In addition, preliminary evaluation of the efficacy as well as 
safety/tolerability and PK for NOX66 will be made in combination with doxorubicin in patients 
with metastatic STS. Although doxorubicin is used as first line therapy in this disease, median 
survival is still only about 1 year and there is significant toxicity. Based on nonclinical data as 
noted in Section 6.2 the effectiveness of doxorubicin could be enhanced in the presence of 
NOX66. 
Additional information on NOX66 may be found in the Investigator’s Brochure. 
6.2 CHOICE OF COMPARATOR OR CONTROL 
The present study is designed to find the maximum tolerated dose (MTD) of the combination 
of NOX66 with doxorubicin in patients with STS, and therefore no control group or 
comparator is needed for this study.   
All patients will be treated with doxorubicin which is widely held as the initial standard of care 
for metastatic STS. One week prior to initiation of doxorubicin, patients in the Dose-Escalation 
Cohorts will also receive 7 days of NOX66 monotherapy which has been shown to be cytotoxic 
to sarcoma cell lines (n=19) in vitro with IC50 values ranging from 0.3 to 18.4 µM (median 
5.2 µM).  
In the Dose Expansion Cohort, all patients will be treated for 1 day with NOX66 (at the MTD 
of the combination of NOX66 and doxorubicin), before receiving doxorubicin on Day 2 of a 
21-day cycle. On Days 2 to 7, NOX66 will be given at the same dose as on Day 1. No therapy 
is administered from Days 8 to 21 of each treatment cycle. 
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7 STUDY OBJECTIVES 
7.1 PRIMARY OBJECTIVES 
• To estimate the maximum tolerated dose (MTD) of NOX66 in combination with 
doxorubicin 
• To characterize the safety and tolerability of NOX66 alone and in combination with 
doxorubicin.  
7.2 SECONDARY OBJECTIVES 
• To determine single-and multiple-dose pharmacokinetics (PK) of idronoxil  
• To determine the preliminary efficacy and quality of life (QOL) of the MTD of NOX66 
in combination with doxorubicin. 
7.3 EXPLORATORY OBJECTIVES 
• To investigate the relationship between response to NOX66 plus doxorubicin and the 
following: 
o Dose of NOX66 
o Histopathology (if prior tissue samples/slides are available) 
o Genetic mutations 
o Cytokine/chemokine and ENOX2 dynamics 
o Change in lipid profile from baseline Acceptability of NOX66 dosage form 
8 STUDY DESIGN AND OVERALL INVESTIGATIONAL PLAN 
8.1 OVERALL INVESTIGATIONAL PLAN 
This is a Phase I, open label, dose escalation and dose expansion study of NOX66 given 
rectally, in cohorts of patients with metastatic STS who have not been exposed to 
anthracycline therapy, using a fixed dose escalation schema every 21 days to establish the 
MTD of the combination of NOX66 and doxorubicin.   
8.1.1 DOSE-ESCALATION  
For all dose escalation cohorts, there will be 7 days of monotherapy treatment with NOX66 
followed by a 5- day washout period prior to the start of combination cycles of NOX66 and 
doxorubicin. The purpose of the monotherapy treatment is to evaluate the safety and 
tolerability of NOX66 when administered alone and as well as single and multiple dose PK of 
idronoxil. 
The dose-escalation part of the study will include three planned Treatment Groups (800, 
1200, 1800 mg daily) of 3 patients each. The first 3 patients will be entered at Dose Level 1 
and will receive daily doses of NOX66 for 7 days.  All of these doses, except for the 1800 mg 
have been evaluated in 2 previous clinical trials and have been relatively well tolerated as 
monotherapy for 14 days and in combination with carboplatin for 42 days. 


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After a rest period of 5 days and if no significant toxicities (DLT equivalent toxicity) have 
occurred, patients will enter the combination therapy part of the study which will consist of 
up to 6 x 21-day treatment cycles. Each cycle will consist of 7 days of NOX66 (at the assigned 
dose), doxorubicin (75 mg/m2) on Day 2 of the 21-day cycle (administered at approximately 1 
hour after rectal application of NOX66) and a rest period of 2 weeks.  
For the 800 mg and 1200 mg dose levels NOX66 will be administered twice-daily (BID)  with a 
400 mg or 600 mg suppository, respectively, and the 1800 mg dose level will entail 
administration of a 600 mg suppository three times daily (TID). In all cohorts, doxorubicin will 
be given initially at 75 mg/m2 as an intravenous infusion over 15 minutes (or as per standard 
of care). This dose may be reduced to 60 mg/m2, at the Investigator’s discretion for 
unacceptable Grade >2 toxicity. A dose reduction of 50% is recommended if serum bilirubin 
is 1.2 -3.0 mg/dL prior to a cycle. If serum bilirubin is 3.1-5.0 mg/dL prior to a cycle, a 75% 
dose reduction of doxorubicin is recommended. 
The MTD of the combination of NOX66 and doxorubicin will be determined over the first 21-
day interval (Cycle 1) following monotherapy with NOX66 and in combination of doxorubicin-
in 1 of 3 consecutive dose cohorts. The MTD of the combination will either be considered 
one dose level of NOX66 lower than the dose which produces ≥ 2 DLTs in 3 or 6 patients, 
depending if a DLT occurred in the first 3 patients, or the highest dose level tested (1800 mg 
daily) if the aforementioned condition does not occur. A DLT will be defined as a protocol-
specified adverse event of toxicity Grade 3-4 (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE] V 5.0) which is considered possibly, 
probably, or definitely related to the combination of NOX66 and  doxorubicin (Section 8.3).  
Since this is a multicenter trial, the sites are to notify the Sponsor or designee when a patient 
has been declared eligible to participate. After 3 patients have completed a 21-day treatment 
cycle of the combination of NOX66 and doxorubicin and all the safety data are available, 
assessment of toxicities and decisions about dose escalation and cohort expansion (see 
below) will be made by the SRC, which will include at least one Sponsor representative 
participating Investigators, and may also include a cardiologist or other external consultants 
at the Sponsor’s discretion. Recommendations from the SRC could include 1) repeat a dose 
level, 2) await further safety data if follow-up is pending for patient(s) as determined by the 
Investigator(s), 3) discontinue the study, 4) escalate the dose to next possible level or 5) take 
other actions. 
Three new patients will be entered at the next dose level of NOX66, if there were no DLTs or 
only 1 of 6 patients had a DLT at the end of the first cycle.   
If no DLT is observed at 1800 mg (Cohort 3), dose escalation will be stopped. The proposed 
highest dose level (1800 mg) will be declared the MTD, and additional patients will be 
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8.1.2 COHORT EXPANSION 
After the dose escalation part is completed, 16 patients will be enrolled into a Dose Expansion 
Cohort at the MTD of the combination. All patients will enter directly into 21-day combination 
cycles and will be given NOX66 therapy for 7 days and doxorubicin will be administered on 
Day 2. This will be followed by a 2-week rest period. Treatments will continue up to 6 cycles.  
For both the Dose Escalation and Cohort Expansion groups, treatment will be terminated 
upon disease progression, unacceptable toxicity or a maximum of 6 cycles. In patients who 
develop Grade 3 or 4 toxicity determined to be related to NOX66, the Investigator may reduce 
the dose or frequency of dosing by one level so that the patients can remain in the study.  
Furthermore, all patients will be actively followed up for about 14 months after completion 
of Cycle 6 (including scheduled visits every 3 months) followed by telephone follow-up/chart 
review, for PFS and OS, at 15 and 18 months from the start of Cycle 1. 
8.2 STUDY TREATMENTS 
Idronoxil is a multiple-signal transduction regulator which results in cell death via extrinsic 
and intrinsic apoptosis, anti‐angiogenesis, and immunomodulation via stimulation of natural 
killer cell activity. The study drug (NOX66) is formulated in a single use suppository with a 
proprietary lipophilic base containing 400 or 600 mg of idronoxil. The suppository will be self-
administered by each patient according to the dose level assigned. 
Doxorubicin is a cytotoxic anthracycline antibiotic that binds to nucleic acids, presumably by 
specific intercalation of the planar anthracycline nucleus with the DNA double helix. 
Doxorubicin hydrochloride for Injection, USP, a sterile red-orange lyophilized powder for 
intravenous use only, is available in 10, 20 and 50 mg single dose vials and a 150 mg multidose 
vial. It is recommended that doxorubicin be slowly administered into the tubing of a freely 
running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, 
USP. The tubing should be attached to a Butterfly® needle inserted preferably into a large 
vein. Prior to the start of each cycle, patients must have a minimum ANC of 1000/μL3 to reduce 
the risk of infection from suppository insertion. 
8.3 DEFINITION AND DETERMINATION OF MTD AND DLT 
8.3.1 DEFINITION OF MTD 
The MTD is defined as the maximum dose level at which no more than 1 patient out of 6 
experienced a DLT at the end of Cycle 1. 
8.3.2 DETERMINATION OF MTD 
If at any given dose level, when 1 of 3 patients develops a DLT during Cycle 1, then the dose 
escalation will halt temporarily, and an additional 3 patients will be recruited at the same 
dose level. If no further DLTs occur, then dose escalation will resume with the next 3 patients 
receiving the next higher dose of NOX66. If there are 2 or more patients (out of 6) who 


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experience DLTs during Cycle 1, dose escalation will be halted, and that level will be declared 
the DLT dose level. The previous dose level will then be considered for expansion to 6 
patients in order to confirm that it is the MTD level. If in the first group at 800 mg, 2 or 3 
patients develop DLTs then that dose level is considered to be the DLT level and 3 additional 
patients need not be tested at that level, but lower doses should be studied. 
8.3.3 DEFINITION OF DLT 
Any of the following, if judged to be associated with the combination of NOX66 and 
doxorubicin (i.e., possibly-, probably-, or definitely related), during Cycle 1, at each dose 
level, will be considered a DLT using the NCI-CTCAE Version 5.0: 
1) Grade 3 non-hematological toxicities (excluding alopecia) with the following 
exceptions: 
i. Grade 3 nausea/vomiting or diarrhea <72 hours with adequate antiemetic and other 
supportive care 
ii.  Grade 3 fatigue <1 week 
iii. Grade 3 electrolyte abnormality that lasts 24 to 72 hours (Investigator’s discretion 
for timeframe), is not clinically complicated and resolves spontaneously or responds 
to conventional medical interventions. 
2) Grade 4 non-hematologic (non-laboratory) toxicity of any duration  
3) Grade 3 or Grade 4 febrile neutropenia of any duration not caused by doxorubicin. It 
is well known that a dose-dependent, reversible leukopenia and/or neutropenia are 
the predominant manifestations of doxorubicin hematologic toxicity and are the most 
common acute dose-limiting toxicities of this drug. With the recommended dose 
schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after 
treatment with recovery usually occurring by the 21st day.  
4) Grade 3 thrombocytopenia in combination with a Grade 3 or greater blood and 
lymphatic system disorder, not attributable to doxorubicin 
5) Grade 3 AST or ALT that is associated with a Grade 2 or greater rise in bilirubin 
Based on the limited experience with NOX66 and the known toxicities of doxorubicin, it is 
possible that there may be overlapping toxicities in terms of anemia, neutropenia, nausea, 
and asthenia.  
If patients develop any DLT during NOX66 monotherapy and/or during Cycles 2 to 6 of the 
combination, these will be considered “DLT equivalent toxicity” and will be recorded in the 
eCRF. Growth factor support (except during Cycle 1 in the Dose Escalation Cohorts) or other 
supportive medication (anti-emetics) at any cycle may be given at the discretion of the 
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8.3.4 DETERMINATION OF DLT 
At the end of Cycle 1, all patients in each cohort will be evaluated for DLTs for dose escalation 
of the next cohort. During the other cycles, assessment of DLTs will be done on an ongoing 
basis, and if they arise, the doses of NOX66 or doxorubicin or both may be reduced. If a new 
DLT is most likely related to doxorubicin, the dose of doxorubicin should be reduced to 
60 mg/m2 or to 37.5 or 18.75 mg.m2 (based on serum bilirubin) or delayed until toxicity has 
been resolved or improved. If the DLT is likely related to NOX66, the Investigator may lower 
the NOX66 dose and/or extend the dosing interval.  
8.3.5 EVALUABLE PATIENT 
The criteria for determination of an evaluable patient for a dose escalation decision or 
determination of MTD, must include: 
• Patient who experienced a DLT during the 21-day combination treatment cycle 
(Cycle 1) or 
• Has not experienced a DLT and has taken at least 80% of the prescribed daily doses 
of NOX66 and completed all safety evaluations required in Cycle 1  
8.3.6 PATIENT REPLACEMENT 
The following guidelines will be used to determine when a patient can be replaced  
• 
During the Monotherapy period in the Dose Escalation part of the study, if a patient 
who is not tolerating the assigned dose of NOX66, may be replaced with another 
patient, following a joint decision between the Investigator and Medical Monitor. A 
maximum of 3 replacements is allowed in each dose level in the Monotherapy 
period.  
• If any patient withdraws consent during Monotherapy period or during Cycle 1, 
he/she will be replaced with another patient.  
• If any patient who has not taken at least 80% of the prescribed daily doses of NOX66 
during Monotherapy period and Cycle 1, will be replaced with another patient. 
• During the Dose Expansion Part, patients who have not completed at least 2 
complete cycles of treatment, will be replaced with additional patients, until at least 
12 patients have completed 2 cycles.  
The recommended phase 2 dose (RP2D) may be defined as the highest dose of the 
combination administered if no DLTs are observed and the dosage form is acceptable to 
patients.  
9 STUDY PARTICIPANTS 
9.1 STUDY POPULATION 
Up to approximately 34 patients with metastatic STS will be studied. Patients will be selected 
at cancer centers that have a sufficient number of sarcoma patients who would be willing to 
participate in clinical trials, and the center is equipped to provide rapid, comprehensive 


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treatment for different types of sarcoma. The Investigators chosen for this study must have 
expertise in the treatment of sarcoma as well as in the administration of doxorubicin. 
9.2 INCLUSION CRITERIA 
Patients must satisfy all of the following criteria to be included in the study: 
1. Adult patients (≥18 years of age, inclusive at the time of signing the informed consent) 
with histologically confirmed diagnosis of metastatic or recurrent STS (histopathology, 
i.e., type of sarcoma and grade needs to be recorded). 
2. Patients for whom treatment with doxorubicin is considered to be appropriate 
(hemoglobin > 10 g/dL, ANC > 1000/μL3, and platelets > 100,000/μL3), serum bilirubin < 
1x the institutional upper limit of normal (ULN) (unless known Gilbert’s disease), AST or 
ALT < 3x institutional ULN, and creatinine clearance ≥50 mL/min as determined by the 
Cockcroft-Gault equation. The laboratory normal ranges for clinical laboratory tests must 
be sent to the Sponsor/CRO before the study is initiated at each site. 
3. Left ventricular ejection fraction ≥ 50%. 
4. Disease that is considered measurable according to RECIST v1.1. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.  
6. Anticipated life-expectancy of at least 6 months.  
7. For females of reproductive potential the following are considered highly effective 
acceptable forms of contraception: surgical sterilization (tubal ligation); total abstinence 
from sexual intercourse with the opposite sex; established hormonal birth control (e.g., 
oral, transdermal, injection, or implant) plus a barrier method or a double barrier method 
(intrauterine device, spermicide, or diaphragm plus condom) for at least 1 month prior to 
screening and agreement to use such a method during study participation and for an 
additional month after the last dose of NOX66 or 6 months after the last dose of 
doxorubicin, whichever is longer.  
8. For males of reproductive potential: vasectomy or use of highly effective contraception 
(e.g., condoms, abstinence) during the study and until 3 or 6 months after the last dose of 
NOX66 or doxorubicin, respectively, whichever is longer.  
9.3 EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be disqualified from entering the study: 
1. Histologically or cytologically confirmed Kaposi’s sarcoma, gastrointestinal stromal tumor 
(GIST), extra-skeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, and 
desmoid tumor.  
2. Hepatic impairment defined as serum bilirubin > 1x ULN (unless known Gilbert’s disease) 
or either AST or ALT > 3x institutional ULN. 
3. Unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 6 months 
before study entry. 
4. Untreated metastases to the CNS. 
5. Received previous treatment with anthracyclines and anthracenediones. 


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6. Previous radiation therapy to the mediastinal or pericardial area. 
7. A known allergy to any of the treatment components. 
8.  Active or chronic infection with human immunodeficiency virus (HIV). 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. Pregnant (positive urine pregnancy test) or lactating. 
10. Patient not willing to use suppositories. 
11. Patients with a colostomy.  
12. Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis 
13. Patients for whom administration of the suppositories are likely to cause pain (e.g., 
inflamed hemorrhoids, fissures, or lesions of the anus or rectum). 
14. Patients with fecal impaction, chronic idiopathic constipation, or chronic diarrhea or 
alternating irritable bowel disease. 
15. Patients with inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis). 
16. Previous treatment with an investigational agent or the non-approved use of a drug or 
device within 4 weeks before study entry.  
17. Uncontrolled diabetes mellitus. 
18. Patients who require concomitant use of inhibitors or inducers of CYP3A4, CYP2D6 or 
P- glycoprotein (P- gp). 
9.4 STUDY WITHDRAWAL CRITERIA 
Patients will be withdrawn from the study if any of the following occurs; 
• Patient withdraws consent 
• Death 
9.5 TREATMENT WITHDRAWAL CRITERIA 
Treatment with NOX66 or doxorubicin will be withdrawn if one or more of the following 
occurs: 
• Disease progression based on RECISTv1.1 
• An inter-concurrent illness that prevents further administration of NOX66 
• An adverse event that is intolerable to continue the treatment with NOX66 and 
doxorubicin or any DLT (Section 8.3) that has not resolved to Grade 1. 
• Cardiac toxicity, e.g., if there is an absolute decrease in left ventricular ejection 
fraction (LVEF) of >10% from the previous evaluation, or if the actual LVEF decreases 
to ≤40%, requires doxorubicin to be discontinued. Doxorubicin must also be 
discontinued if the patient develops Grade 3 or 4 left ventricular systolic dysfunction 
(symptomatic congestive heart failure). 
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In all cases, the reason for study or treatment withdrawal, either at the patient’s request or 
at the Investigator’s discretion, and the date of last dose of NOX66 and doxorubicin, must be 
recorded in the electronic case report form (eCRF) and in the patient’s medical records. The 
patient must be followed to establish whether the reason was an adverse event causally 
related to NOX66, and, if so, this must be reported in accordance with the procedures in 
Section 11.3. 
Any patient who appears to be noncompliant should be counselled but not withdrawn from 
the study in Cycles 2 to 6.  
10 STUDY MATERIALS 
10.1 STUDY PRODUCT 
10.1.1 INVESTIGATIONAL PRODUCT FORMULATION AND DESCRIPTION 
NOX66 is idronoxil formulated in two strengths in a proprietary lipophilic base to yield 
suppositories with a nominal weight of 2.2 or 3.3 g containing either 400 or 600 mg drug 
substance, respectively. 
10.1.2 INVESTIGATIONAL PRODUCT PRESENTATION, STORAGE AND HANDLING 
NOX66 is packaged with each suppository individually sealed in plastic packaging and boxed 
as quantities to meet the need of the treatment cycles under investigation. The drug product 
is stored refrigerated (2 – 8 °C). For each treatment period and cycle, the appropriate number 
of suppositories will be dispensed with at least enough for 1 extra day of treatment to account 
for misplaced or lost study drug.  
10.1.3 INVESTIGATIONAL PRODUCT LABELLING 
NOX66 suppositories will be packaged by the Sponsor and supplied in an open label basis. The 
primary plastic container which contains the suppository units will be labelled as follows: 1) 
Sponsor’s name and address, 2) Study number, 3) Name of the product, 4) Lot Number, 5) Re-
assay date, 6) Storage conditions, 7) Dosage and 8) Caution Statement: “New Drug--Limited 
by Federal (or United States) law to investigational use." The plastic container will be 
packaged in a box. 
10.1.4 DOXORUBICIN, GROWTH FACTORS, DEXRAZOXANE 
For details on doxorubicin see Section 8.2. The use of growth factors and dexrazoxane is 
permitted to reduce myelosuppression and cardiac toxicity due to doxorubicin. Growth 
factors may be used to treat neutropenia and thrombocytopenia in all cycles in the Dose 
Escalation and Expansion Cohorts (except for Cycle 1 in the Dose Escalation Cohorts). The 
degree of myelosuppression may be increased at Cycles 5 and 6 with the use of 
dexrazoxane. Doxorubicin should be given within 30 minutes after beginning the infusion 
with dexrazoxane. [Note: For breast cancer patients, dexrazoxane is recommended when 
doxorubicin cumulative dosage is ≥ 300 mg/m2]. 
 


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These products will be obtained as standard of care and are prescribed based on the 
Investigator’s clinical judgement. 
10.2 INVESTIGATIONAL PRODUCT ADMINISTRATION 
10.2.1 ADMINISTRATION 
Depending on the cohort/dose level, 2 to 3 suppositories will be self-administered daily for 
7 days in the Monotherapy period (only for Dose Escalation part) and/or in combination with 
doxorubicin for the treatment cycles. In this study, the dosage forms will be inserted rectally 
either twice (12 hours apart) or three times (8 hours apart) per day. In patients who have 
regular bowel movements (i.e. within several hours after awakening) patients will be 
instructed to insert the suppository after the bowel movement. To promote regular 
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. If defecation occurs after NOX66 administration, no re-dosing is required. The next 
dose should be administered at the scheduled time. During the NOX66 and doxorubicin 
combination treatment cycles, if diarrhea occurs, the Investigator must follow standard 
management practices to manage the diarrhea to allow for NOX66 administration.  
If any patients have difficulty with administering suppositories three times per day (8 hours 
apart) due to any personal reasons, dosing schedule can be changed to two times daily (3 
suppositories per day) after Cycle 2. In this instance, patients can administer one 600-mg 
suppository in the morning and two 600-mg suppositories in the evening. While two 
suppositories are administered, each suppository needs to be inserted at least 5 minutes 
apart.  
The dosing time for each suppository must be recorded by the patient in a diary which must 
be brought to the clinic at each visit. The dose escalation scheme is presented in Table 1 
 
Proposed Starting Dose and Dose Escalation Scheme for NOX66 
Table 1 
Proposed Starting Dose and Dose Escalation Scheme for NOX66 
Cohort 
1 
2 
3 
Increment 
NA 
50% 
50% 
Total daily dose (mg) 
800   
1200 
1800   
Daily regimen (mg) 
400 BID 
600 BID 
600 TID 
10.2.2 DURATION OF THERAPY 
In the Dose Escalation part of the study, the duration of therapy for NOX66 alone is one week. 
After an off-treatment for 5 days, combination therapy with doxorubicin will be initiated and 
on Day 1 of Cycle 1, NOX66 will be administered at the same dose level as in the Monotherapy 
period. Doxorubicin (75 mg/m2) will be administered on Day 2 of Cycle 1. This is followed by 
an off-treatment period of 2 weeks and then Cycle 2 will be initiated in the same manner as 


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for Cycle 1. Up to 6 cycles of doxorubicin can be administered and up to 7 weeks of NOX66 
can be administered during this study. 
For the Dose Expansion Cohort, patients will enter Cycle 1 of combination therapy and receive 
NOX66 for 7 days and on Day 2 they will receive doxorubicin. This will be followed by a 2-
week rest period before starting the next cycle with a maximum number of 6 cycles. 
10.2.3 DOSE MODIFICATIONS 
The dose of doxorubicin can be reduced from 75 to 60 mg/m2 if a Grade 2 toxicity related to 
doxorubicin occurs. If serum bilirubin is 1.2-3.0 mg/dL prior to a cycle, a 50% dose reduction 
of doxorubicin is recommended. If serum bilirubin is 3.1-5.0 mg/dL prior to a cycle, a 75% 
dose reduction of doxorubicin is recommended. 
If a perineal and/or anal rash develops (Grade 1-2), a topical hydrocortisone containing 
haemorrhoid cream/ointment and/or cutaneous cream should be used. For Grade 3-4 
perineal and/or anal rash, NOX66 treatment should be delayed until the rash resolves to 
Grade 1 or completely. NOX66 should also be delayed if there is proctitis, rectal mucositis, or 
ulcer of Grade 2 or higher. Treatment may be resumed when toxicity decreases to Grade 1. 
Treatment with NOX66 should also be delayed in the presence of anorectal infections and 
may be resumed after they are resolved.  
All dose delays for NOX66 and doxorubicin need to be discussed with the Medical Monitor.  
For patients developing neutropenia, the following guidelines should be used for doxorubicin 
dose modification. 
Toxicity 
Recommended Dose Modification 
ANC < 1,000 
No doxorubicin administered; treatment cycle 
delayed 
≥ Grade 3 neutropenic fever/infection  
Approximately 60 mg/m2 doxorubicin 
≥ Grade 4 neutropenia lasting longer than 1 week  
Approximately 60 mg/m2 doxorubicin 
Second incidence of either:  
1) ≥ Grade 3 neutropenic fever/infection  
2) Grade 4 neutropenia lasting longer than 1 week 
Second dose reduction to 45 mg/m2 
Reversible Grade 3 neutropenia with fever/infection or 
Grade 4 ANC  
Retreatment with doxorubicin at Investigator’s 
discretion  
Abbreviation: ANC = absolute neutrophil count 
In the event of cardiac toxicity (e.g., if there is an absolute decrease in LVEF of >10% from the 
previous evaluation, or if the actual LVEF decreases to ≤40%) doxorubicin must be 
discontinued. Doxorubicin must also be discontinued if the patient develops Grade 3 or 4 left 
ventricular systolic dysfunction (symptomatic congestive heart failure). 


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Patients who discontinue doxorubicin after 4 cycles of treatment should complete the 
remaining 2 cycles of NOX66 as planned. If doxorubicin is discontinued prior to 4 cycles, 
NOX66 treatment may continue in consultation and agreement with the Medical Monitor.  
10.3 ACCOUNTABILITY FOR CLINICAL SUPPLIES 
The Investigator or designee will be responsible for the dispensing, inventory, and 
accountability of all clinical supplies, exercising accepted medical and pharmaceutical 
practices at his/her institution. An accurate and timely accountability record log of the 
disposition of all clinical supplies must be maintained. The supplies and inventory record must 
be made available for inspection by the Sponsor or the designated Sponsor’s representative 
upon request. All unused medication along with the medication box will be collected and 
retained until the drug accountability is performed by a Sponsor representative. Once all drug 
accountability has been performed the Investigator will destroy NOX66 as per Site Pharmacy 
SOPs and/or return all remaining clinical supplies to the Sponsor who will destroy the study 
drug on the site’s behalf. Under no circumstances will the Investigator or other staff members 
allow NOX66 to be used other than as directed by this protocol. 
10.4 CONCOMITTANT THERAPIES 
Medications (prescription and non-prescription, including vitamins and supplements) taken 
for the treatment of stable chronic conditions within 30 days before Screening will be 
recorded. All concomitant medications will be recorded on the eCRF. Every effort will be made 
to keep the daily dose of the concomitant medications needed for the treatment of chronic 
conditions during the NOX66 monotherapy and combination with doxorubicin unchanged 
throughout the study. Treatment of acute conditions will be made as medically indicated (e.g., 
infection). Growth factor support can be administered during any combination cycle, except 
during Cycle 1 in the Dose Escalation Cohorts. Anti-emetics are permitted prior to the 
administration of doxorubicin. 
The following medications and products will be prohibited: 
• Inducers (phenobarbital) and inhibitors (valproic acid, probenecid, atazanavir, 
gemfibrozil, indinavir) of Phase II drug metabolizing enzymes are prohibited within 14 
days prior to first dose of NOX66 and during the combination treatment period.   
• Strong inducers and inhibitors of cytochrome P450 CYP3A4, CYP2D6, and P-gp within 14 
days prior to first dose of doxorubicin and during the combination treatment period. If 
patients are already taking these medications at Screening every effort should be made 
to switch to an alternative medication that does not inhibit these enzymes within 14 days 
prior to the first dose of doxorubicin.   
• Doxorubicin is a moderate CYP2B6 inhibitor and, therefore could potentially increase the 
pharmacological effects of drugs that are CYP2B6 substrates (e.g., promethazine, 
propofol,selegiline).http://www.bccancer.bc.ca/drug-database-
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• Based on in vitro data, idronoxil may inhibit the activity of CYP2C8, 2C9, 2C19 and 3A4 
enzymes in human microsomes in a range of 0.457–3000 μM and concomitant medication 
that is metabolized by these enzymes should be used with caution. 
• A list of known inhibitors and inducers of CYP450 enzymes is provided in Section 22.3. 
• Food or beverages that could potentially interfere with P-gp transport, such as those 
containing, but not limited to, grapefruit, Seville orange, tangerine, mango, guava, or 
watercress; and those that could potentially interfere with CYP3A, such as those 
containing, but not limited to, grapefruit juice, grapes, cranberry, pomegranate, mango, 
black raspberry, or black mulberry, should not be consumed 14 days prior to the first dose 
of NOX66 and during the study. Examples of drugs that can inhibit P-gp include 
cyclosporine, ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, and verapamil. 
Inducers of P-gp activity include rifampicin, carbamazepine, St. John’s wort, and 
tipranavir. 
11 STUDY PROCEDURES AND FLOW CHART 
11.1 OUTCOME MEASURES 
11.1.1 PRIMARY ENDPOINTS 
Safety parameters will be expressed as change from baseline, mean and median values (when 
appropriate) and include the following: 
• Adverse events and concomitant medications 
• Electrocardiogram (ECG parameters [obtained by standard 12-lead recordings], including 
clinically significant abnormalities in ECG rhythm and waveform morphology reported as 
TEAEs,  
• Changes in echocardiographic parameters  
• Brain type natriuretic peptide (BNP) and troponin I levels 
• Clinical laboratory assessments to include serum chemistry, hematology, and urinalysis 
• Vital signs (blood pressure, pulse, respiration rate, body temperature) 
• Physical examination findings 
11.1.2 SECONDARY ENDPOINTS 
11.1.2.1 Pharmacokinetics 
Blood concentrations of idronoxil and idronoxil metabolites and plasma concentrations of 
doxorubicin and doxorubicinol will be assayed by validated methods by a central laboratory. 
PK parameters of idronoxil and metabolites, will be determined using non-compartmental 
analyses after administration of idronoxil on Days 1 and 7 during monotherapy in the Dose 
Escalation Part and include:  
• Cmax  
Maximum observed blood drug concentration 
• Tmax 
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• AUC-last 
Area under the blood concentration time curve (AUC) from time 0 to the last 
measurable concentration 
• AUCτ 
AUC from time 0 to end or dosing interval (τ) 
• AUCinf 
AUC from time 0 to infinity (if possible) 
• kela 
Terminal elimination rate constant, calculated from a semi-log plot of the 
blood concentration versus time. The parameter will be calculated by linear least squares 
regression analysis using the maximum number of points in the terminal log-linear phase 
(e.g., 3 or more nonzero blood concentrations). 
• T1/2a 
Terminal elimination phase half-life, calculated as 0.693/kel (if possible) 
aNote: No value for kel, or T1/2 will be reported for cases that do not exhibit a terminal log 
linear phase in the concentration versus time profile. Additional blood PK parameters may be 
calculated if deemed appropriate. 
For the Dose Escalation Part, during the combination cycles, 1 to 4 PK samples will be obtained 
on Days 2, 7, and 8 to assess concentrations of idronoxil and metabolites or doxorubicin and 
doxorubicinol. For the Dose Expansion Part, 1 to 3 PK samples will be obtained on Days 2 and 
7 to assess concentrations of idronoxil and metabolites or doxorubicin and doxorubicinol.  
Comparisons will be made to assess the degree of inter-and intra-patient variability during 
the study. 
At the discretion of the Sponsor, non-evaluable concentrations or parameters may be 
excluded from the final PK analysis dataset. Any data exclusions will be documented in the 
final study report. The relationship between PK parameters and adverse events and other 
safety findings will be explored. 
11.1.2.2 Efficacy (Secondary Analysis) 
Tumor response will be assessed by RECISTv1.1 criteria (21) at the end of Cycles 2, 4 and 6 
and at Months 6, 9 and 12 and at the End of Study to determine: 
• Disease Control Rate ((SD+PR+CR)/All) 
• Objective Response Rate [ORR]((PR+CR)/All) 
• Complete Response (CR) 
• Partial Response (PR)  
• Stable Disease (SD) 
• Progressive Disease (PD)  
The following time to event endpoints will also be assessed: 
• Progression free survival (PFS) 
• Overall survival (OS) 
11.1.2.3 Quality of Life (Secondary Analysis) 
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• European Organization for Research and Treatment of Cancer: Core Quality of Life 
Questionnaire v3.0) (EORTC QLQ-C30) 
• Fatigue Severity Scale (European Organisation for Research and Treatment of Cancer: 
Cancer Related Fatigue Module - EORTC QLQ-FA12)  Brief Pain Inventory – Short Form 
(BPI-SF)  
11.1.2.4 Exploratory Analysis 
Factors which may contribute to the overall response to the combination of NOX66 and 
doxorubicin will be evaluated and include.  
• NOX66 dose or exposure  
• Doxorubicin exposure 
• Histopathology 
• Cytokine and chemokine response 
• ENOX2 response 
• Specific genetic mutations 
• Lipidomic profiling (capturing over 300 lipid species as determined by liquid 
chromatography-tandem mass spectrometry) 
• Suppository Acceptance Questionnaire 
For the safety and efficacy parameters, these are the standard measures used to assess the 
effects of a novel chemotherapeutic agent alone and in combination with a cytotoxic agent 
like doxorubicin. The safety profile of doxorubicin is well known and greater 
myelosuppression, or unexpectedly elevated levels of AST, ALT, and bilirubin than what one 
would expect with this agent given alone is suggestive of an additive effect from NOX66. The 
assessments of cardiac function with echocardiograms and biomarkers BNP and troponin 1 
are well established to detect potential doxorubicin induced cardiac toxicity. 
11.2 RECRUITMENT 
METHOD ASSIGNING SUBJECTS TO TREATMENT GROUPS 
Patients will be recruited from several sites in the US and Australia that are referral centers 
for patients with STS. Sites must confirm with Sponsor/CRO before consenting any patient on 
slot availability for Dose Escalation Cohorts. Once eligibility is confirmed by the Investigator 
or designee via a Patient Enrollment Form, the next available patient number will be assigned 
within a cohort (Section 12.1). The Investigator must not prescribe or administer the study 
drug until the patient’s enrollment is approved by Sponsor/CRO, informed consent has been 
signed, and the patient has been assigned to a cohort. 
The Sponsor/CRO will maintain a log of the number of patients at each dose level, the 
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11.2.2 
TREATMENT DISCONTINUATION 
Patients will be discontinued from the study treatment if any of the following occurs as noted 
in Section 9.5. 
• Disease progression based on RECISTv1.1 
• An inter-concurrent illness that prevents further administration of NOX66 
• An adverse event that is intolerable to continue the treatment with NOX66 and 
doxorubicin or any DLT (Section 8.3) that has not resolved to Grade 1. 
• Any other reason the Investigator considered that impacts the patient's safety. 
For the patients who discontinue treatment, they will continue on study for follow-up visits 
for tumor evaluation. All anti-cancer treatments should be recorded in the eCRF. In those 
patients who have evidence of disease progression during the combination of NOX66 and 
doxorubicin, additional tumor evaluation assessments are not needed. 
If a patient is withdrawn from the study at any time, either at his/her request or at the 
Investigator’s discretion, regardless of the reason, the Investigator will record on the relevant 
page of the eCRF the reason(s) for withdrawal and the day of last dosing. The eCRF (and the 
clinical study report) will include reasons for patient withdrawals, as well as other details 
relevant to the patient’s withdrawal.    
Any patient who appears to be noncompliant from Cycles 2 to 6 should be counselled but not 
withdrawn from the study. Patients who discontinue for non-safety related reasons or for 
noncompliance prior to the end of Cycle 1 in the Dose-Escalation Part can be replaced.  
Should any patient withdraw or be withdrawn from the study prior to the completion of the 
Month 18 follow-up visit, every effort should be made to complete the assessments at the 
End of Study (Section 11.6.2.12). Patients experiencing adverse events 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. 
Discontinuation due to treatment failure, as defined by disease progression, is to be expected 
since doxorubicin is not curative for sarcoma and the optimal dose and dose frequency is not 
known for NOX66. Alternate treatments for sarcoma may be offered to the patient. 
11.3 STUDY PROCEDURES 
This study will be conducted in three parts each with screening, treatment and follow up 
periods as outlined in Table 2. In the Dose Escalation Part, patients receive NOX66 
monotherapy followed by NOX66 and doxorubicin combination therapy. In the Dose 
Expansion Part, patients receive NOX66 and doxorubicin combination therapy only. Patients 
in each part will be followed post therapy for about 14 months. An overview of phases of the 
study by period is shown below (Table 2 and Figure 1). 


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Table 2  
Treatment Periods  
 
      Dose Escalation Only 
Dose Escalation & Dose Expansion 
Screening 
Monotherapy 
Washout 
Combination 
Treatment 
Cycles#  
6 Cycles X 21 
Days 
Follow-Up from C1D1  
Month 6 
(6 M from C1D1) 
Month 9  
(9 M from C1D1) 
Month 12  
(12 M from C1D1) 
Month 15  
(15 M from C1D1) 
Month 18 EOS  
(18 M from C1D1) 
28 days 
7 days 
5 days 
126 days  
1.8 M from C6D21 
3 M from last f/u 
3 M from last f/u 
3 M from last f/u 
3 M from last f/u 
  
12 days 
4.2 Months 
1.8 Months 
3 Months 
3 Months 
3 Months 
3 Months 
  
1.3 Months 
  
18 Months 
~ 20 Months 
C1D1 = Cycle 1 Day 1; EOS = End of Study; f/u = follow-up, M = month  
#Each combination therapy cycle is 21 days with NOX66 administered on Days 1-7 at a fixed dose and regimen. On Day 2 doxorubicin is administered 
intravenously for 15 minutes at 75 mg/m2. No treatment is administered on Days 8-21. During the follow-up period, neither NOX66 or doxorubicin is 
administered, but other approved or investigational medication for sarcoma may be administered. 
 
 


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Figure 1 
Study Schematic 
 
 
 
 
11.4 CLINICAL ASSESSMENTS 
11.4.1 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
At Screening, demographic and other baseline characteristic will be obtained and include age, 
body weight, height, physical examination, medical and surgical history (with pathology 
review of histology of STS), ECOG performance status, concomitant medication, computer 
tomography/magnetic resonance imaging (CT/MRI) scans to identify measurable tumors. 
11.4.2 SAFETY 
Safety assessments (vital signs, physical examinations, change in concomitant medication, 
ECG recordings, AEs, clinical laboratory results (hematology, biochemistry, and urinalysis)) are 
to be performed at protocol-specified visits, as specified in the Schedule of Assessments 
(Table 4). Additional tests may be done when required.  
11.4.2.1 Vital Signs 
Vital signs (blood pressure, heart rate, oral temperature, respiratory rate) will be assessed 
after single doses of NOX66 as well as after multiple doses in the NOX66 monotherapy period 
and prior to each dose of doxorubicin. All vital signs will be measured after the patient has 
been resting in a sitting position for at least 5 minutes. Blood pressure measurements are to 
be taken in the same non-dominant arm for the duration of the study. 
Vital sign measurements will be repeated manually if clinically significant or 
machine/equipment errors occur. Out-of-range blood pressure, respiratory rate or heart rate 
measurements will be repeated at the Investigator’s discretion. Any confirmed, clinically 
significant out-of-range vital sign measurements must be recorded as AEs. 


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11.4.2.2 Physical Examination 
Complete physical examinations (general appearance, skin, HEENT including heart, lungs, 
abdomen, cervical and axillary lymph nodes, extremities, neurological, musculoskeletal 
systems and perineal and anal region) will be performed at Screening (Days -28 to -1), at 
Monotherapy Day 1 and Day 7, at the beginning of each treatment cycle and at the end of 
Cycle 6 (or Early Termination). Physical examinations will be performed by a medically 
qualified individual. In addition, medical history will be recorded at screening and prior to first 
dose of NOX66. 
Symptom-driven limited physical examinations will be performed as clinically indicated at any 
study visit. All changes that are not present at baseline or described in the past medical history 
and identified as clinically noteworthy must be recorded as AEs.  
Physical examination can be performed 1 day prior to the scheduled visit day. 
11.4.2.3 Cardiac Monitoring 
A 12-lead ECG after 5 minutes of rest in the supine position will be obtained at Screening. In 
the Dose Escalation Cohort, triplicate 12-lead ECGs in close succession at least 1 minute apart 
will be obtained after 5 minutes of rest in the supine position at -0.75, -0.5 and -0.25 hours 
prior to administration of NOX66 and at 1, 2, 5, and 8 hours after the first dose of NOX66 
monotherapy (Day 1).  
On Day 7 of Monotherapy, 12-lead ECGs will be recorded performed in triplicate in the same 
manner and time points as on Day 1. In addition, Holter monitoring, will be conducted from 
8 to 24 hours post NOX66. On Day 2 of Cycle 1, the same evaluation will be done before and 
after administration of NOX66, and Holter monitoring will be performed from 8 to 24 hours 
after NOX66 administration (Dose Escalation and Dose Expansion Cohorts). On Day 2 of Cycles 
2 to 6, (combination of NOX66 and doxorubicin), triplicate 12-lead ECGs will be obtained after 
5 minutes of rest in the supine position at -0.25 hours prior to and at 1, 2, 5 and 8 hours post 
morning dose of NOX66. 
On days when serial ECG readings occur, before electrodes are removed after the initial 
reading, the electrode position is to be marked on the skin with indelible ink and the same 
electrode position used for all subsequent ECGs for each patient. 
The following windows are acceptable for performing the ECGs: 
• +/-5 minutes for pre-dose ECGs required at -0.75, -0.5 and -0.25 hours prior to 
NOX66 administration. 
• +/-10 minutes for post-dose ECGs required at 1 hour and 2 hours after NOX66 
administration. 
• +/-15 minutes for post-dose ECGs required at 5 hours and 8 hours after NOX66 
administration. 
Echocardiography will be assessed at the start of Cycles 3, 5 and at the end of Cycle 6 (or 
Early Termination), and compared to baseline (Screening). 


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If clinically indicated, an additional echocardiograph will be done at Cycle 1 prior to the first 
dose of doxorubicin.  All clinically significant findings that are not present at baseline should 
be reported as AEs.  
Echocardiogram assessment can be performed 1 day prior to the scheduled visit day. 
For any patient with an absolute decrease in LVEF of >10% from the previous evaluation, or if 
the actual LVEF decreases to ≤40%, or ≥ Grade 3 LV systolic dysfunction, doxorubicin must be 
discontinued and echocardiograms are to be performed at 6-month intervals in the post 
treatment phase. 
11.4.2.4 Clinical Laboratory Tests 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed 
in the Schedule of Assessments (Table 4). Clinical laboratory tests (hematology, clinical 
chemistry, urinalysis) will be assessed after 7 days of NOX66 monotherapy and will be 
compared to baseline.  
Assessments of hematology, clinical chemistry, and urinalysis are to be performed prior to 
administration of NOX66 on Day 1 of each Cycle. Hematology and clinical chemistry will also 
be performed on Days 9 and 16 of Cycles 1 to 6, to determine if myelosuppression or other 
toxicity has occurred with either NOX66 or the combination of NOX66 and doxorubicin. Prior 
to each treatment cycle, the same clinical laboratory tests are to be repeated to determine if 
NOX66 can be administered (ANC > 1000/μL3), and to determine if the dose of doxorubicin is 
to be delayed or reduced if a Grade 2 or higher toxicity is present or Grade 1 or higher serum 
bilirubin levels are present. 
Clinical laboratory tests required at Day 1 of Monotherapy and Day 1 of each cycle can be 
performed 1 day prior to the scheduled visit day. 
At screening, renal function will be assessed by the Cockcroft and Gault formula as noted 
below: 
Creatinine clearance (mL/min) = {(140–age(years) x weight(kg)/(72 x serum creatinine  
(mg/dL)} x 0.85 (if female). 
 
 


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Table 3 Clinical Laboratory Assessments 
Hematology 
Serum chemistry 
Urinalysis (dipstick) 
Haematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular hemoglobin 
(MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Red blood cell (RBC) count  
White blood cell (WBC) count 
with differential  
Platelet count 
 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Blood Urea Nitrogen (BUN)  
Bilirubin (total and direct) 
Carbon dioxide (CO2) 
Creatinine 
Sodium 
Potassium 
Chloride 
Calcium  
Phosphate 
Magnesium  
Gamma--glutamyl transpeptidase (GGT) 
Glucose  
Lactate dehydrogenase (LDH)  
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
pH 
Protein 
Glucose 
Blood 
Ketone bodies 
Specific gravity 
Urobilinogen 
Microscopy if needed 
based on dipstick 
result 
Coagulation (Screening Only) 
Pregnancy Tests 
Prothrombin time (PT)/INR  
Activated partial thromboplastin time (PTT)  
Urine human chorionic 
gonadotropin  
Blood samples will be analyzed at a local laboratory. Urine samples will be analyzed by 
dipstick, and a microscopic analysis will be performed if the results of dipstick indicate 
abnormalities to be further investigated by a local laboratory. All laboratory reports must be 
reviewed, signed, and dated by the Investigator. A legible copy of all reports must be filed 
with both the patient's eCRF and medical record (source document) for that visit. Any 
laboratory test result considered by the Investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention). 
Clinically significant abnormal values occurring during the study will be followed until repeat 
test results return to normal, stabilize, or are no longer clinically significant.  
Adverse events (Section 16) and concomitant medications will be recorded throughout the 
entire study. 
11.4.2.5 Other Laboratory Tests 
Plasma levels of BNP and troponin 1 will be measured prior to the first dose of NOX66, Day 7 
of monotherapy and at the beginning of Cycles 1, 3 and 5 and at the end of Cycle 6. 


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Blood samples for chemokines and cytokines will be collected prior to the first dose of 
NOX66*, Day 7 of Monotherapy period (only for Dose Escalation) and at the beginning of 
Cycle 3 and at the end of Cycle 6. 
Blood samples for genetic mutation assessment will be collected prior to the first dose of 
NOX66* and at the end of Cycle 6 (or at Early Termination if this occurs prior to Cycle 6).  
Blood samples for immuno assays will be collected prior to the first dose of NOX66*, Day 7 of 
Monotherapy (only for Dose Escalation) and at the beginning of Cycle 3 and at the end of 
Cycle 6.  
*These samples can be collected during screening period instead of Day 1 if needed, after 
confirming subject eligibility and providing signed informed consent.  
Archived tissue sample (10 unstained slides) will be collected, if available, for 
immunohistopathology analysis. 
The Sponsor may use any leftover samples to 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 stored and used for this optional future research. 
11.4.3 PHARMACOKINETICS 
Sampling timepoints for collection of blood samples for PK analyses are presented in Table 7 
(Section 22.2.2.1). 
Monotherapy 
Following the administration of NOX66 during the Dose Escalation Part on Day 1 of 
Monotherapy, blood samples (1 x 4 mL) will be collected in Potassium Oxalate/Sodium 
Fluoride Vacutainer tubes for PK analysis of idronoxil (and metabolites) at pre-dose and at 1, 
2, 3, 4, 6, 8 and 24 hours post dose. Exact times for dosing and blood sampling will be 
recorded. 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. 
The 24-hour blood sample may be collected at the patient’s home by a visiting healthcare 
provider or in the clinic. 
On Day 7 of the NOX66 Monotherapy period, blood samples will be collected for PK analysis 
of idronoxil from each patient, at pre-dose (within 15 minutes prior to dosing) and at 1, 2, 3, 
4, 6, and 8 hours post dose. The remainder of the daily dose will be administered at 8 or 12 
hours after the first morning dose of NOX66. The last PK sample will be obtained at 8 or 12 
hours after the last dose of monotherapy on Day 8. The 0- to 8-hour samples must be obtained 
in the clinic and the samples obtained on the first day of the washout period (Day 8) will be 
collected at the patient’s home or in the clinic. The exact time the samples are collected post 
dose and the time of last dose prior to collection must be recorded. 
 


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NOX66 and Doxorubicin Combination  
Cycle 1 (Dose-Escalation Cohort) 
On Day 2, PK samples are to be collected prior to and at 1 and 2 hours post NOX66 
administration and assayed for idronoxil and metabolites. For doxorubicin, blood samples (1 
x 4 mL) are to be collected in K2EDTA containing Vacutainer tubes at 0.5, 4, and 6 hours after 
the end of the doxorubicin infusion. On Day 7, PK samples will be obtained just prior to the 
morning dose of NOX66 and on Day 8 at 8 and 12 hours after the last dose on Day 7 for the 
TID and BID regimens, respectively. The exact times of dosing of NOX66 and doxorubicin must 
be recorded and when the blood samples are taken after administration of NOX66 and 
following the completion of the doxorubicin infusion must be recorded. The blood samples to 
be taken on Days 7 and 8 may be collected at the patient’s home or clinic. 
Cycles 2, 4, and 6 (Dose-Escalation Cohort) 
On Day 2, PK samples are to be collected within 15 minutes prior to NOX66 administration 
and at 4 hours post NOX66 administration and assayed for idronoxil and metabolites. In 
addition, PK samples are to be collected at 0.5 and 4 hours after the end of doxorubicin 
infusion and assayed for doxorubicin and doxorubicinol (note: 0.5-hour post-dose 
doxorubicin PK sample is not applicable at Cycle 4). 
Cycles 3 and 5 (Dose-Escalation Cohort) 
On Day 2, PK samples are to be collected 4 hours after the morning dose of NOX66 in the clinic 
for idronoxil and metabolites concentrations. Additional PK samples are to be obtained in the 
patient’s home just prior to the morning dose on Day 7 and on Day 8 at 8 or 12 hours after 
the last dose on Day 7, respectively.   
Cycle 1 (Dose Expansion Cohort)  
On Day 2, PK samples for idronoxil and metabolites are to be obtained, prior to NOX66 and at 
4 and 6 hours post dose and prior to the morning dose on Day 7 at the patient’s home. 
Relative to doxorubicin, PK samples are to be collected at 0.5, 4, and 6 hours after the end of 
the doxorubicin infusion.  
Cycles 2, 4 and 6 (Dose Expansion Cohort)  
On Day 2, PK samples are to be collected within 15 minutes prior to NOX66 administration 
and at 4 hours post NOX66 administration and assayed for idronoxil and metabolites. Samples 
for doxorubicin and doxorubicinol concentrations will be collected at 0.5 and 4 hours after 
the end of doxorubicin infusion. 
 


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Cycles 3 and 5 (Dose Expansion Cohort)  
On Day 2, a PK sample for idronoxil is to be collected at 4 hours after the morning dose of 
NOX66 in the clinic. Another PK sample is to be collected within 15 minutes prior to the 
morning dose on Day 7 at the patient’s home. 
Sampling Handling and Windows for PK Sampling 
Plasma will be prepared from each blood sample within 30 minutes of collection. Details on 
the preparation of plasma samples are provided in Section 22.2.2.1.  
The windows for PK blood sample collection are as follows:  
• For pre-dose (0 hour) blood collection: 15 min before dosing  
• For the 0.5 to 2-hour post dose blood collections: +/- 2 minutes from scheduled blood 
collection.  
• For the 3- to 6-hour post dose blood collections: +/- 5 minutes from scheduled blood 
collection. 
• For the 8- to 24-hour post dose blood collections: +/- 30 minutes from scheduled 
blood collection. 
Pharmacokinetic blood sample collection should have priority over other study assessments. 
For other study assessments, in case the distribution of meals or time for study assessments 
coincide with the sample collection time, the sequence of events should be as follows: ECG, 
blood sampling, and distribution of meals. Deviations from the listed PK windows are 
regarded as protocol deviations.  
11.4.4 EFFICACY 
Treatment responses  
Computer Tomography or MRI will be performed at Screening, prior to the start of Cycles 1 
(only in the Dose Escalation cohorts if the previous scan was done more than 28 days 
previously), at the end of Cycles 2, 4, and 6, at 6, 9 and 12 months after the start of the 
combination therapy and at the End of Study (Month 18) or at Early Termination (ET) if the 
patient discontinues from the trial. Changes in the size and number of target lesions will be 
evaluated using RECIST v1.1 criteria, compared to baseline (Screening) or prior to Cycle 1 scan 
whichever is appropriate. 
Other Outcome Measures  
Each patient’s ECOG Performance status will be assessed at the end of NOX66 monotherapy, 
at the start of Cycle 5 and at End of Study, compared to baseline. Assessments of pain, fatigue 
and QOL will be made at the end of NOX66 monotherapy (fatigue and pain only), on Day 1 of 
each cycle for the combination of NOX66 and doxorubicin, at Months 6, 9 and 12 of the follow-
up period and at the End of Study, compared to baseline. Assessments of acceptance of 
suppository administration will made at the end of NOX66 monotherapy and on Day 1 of each 
cycle for the combination of NOX66 and doxorubicin.  


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11.4.5 PHARMCODYNAMICS 
Changes from baseline in blood/plasma levels of cytokines, chemokines, lipids andENOX2 will 
be assessed on Day 7 of Monotherapy, at the beginning of Cycle 3 and at end of Cycle 6.   
11.5 ASSESSMENT OF DISEASE STATUS 
11.5.1 RADIOLOGIC 
Computer tomography or MRI will be used to assess the size and number of all measurable 
target and non-target lesions as defined in RECIST v1.1. For each patient, the same modality 
must be used at baseline and throughout the study. 
11.5.2 TREATMENT RESPONSE  
Assessment of treatment response: Treatment response will be separately assessed at the 
end of Cycles 2, 4, and 6 and End of Study compared to baseline. The RECIST v 1.1 criteria will 
be used to evaluate tumor responses to determine 1) Disease Control Rate (DCR) defined as 
[(stable disease (SD) + partial response (PR) + complete response (CR)/All)], b) overall 
response rate (ORR)(PR+CR)/All), c) OS and d) PFS.  
All radiologic images will be reviewed by an independent, experienced, local radiologist to 
assess RECIST response. The same radiologist should review each patient’s scan.  
11.6 STUDY VISITS 
The study activities and procedures are summarized in Table 4. Details of study procedures 
are provided in this section. A visit schedule for the period projected from the date of first 
dose of study drug to the date of the final Treatment Period Visit should be established for 
each patient by study site staff. 
11.6.1 SCREENING (DAYS -28 TO -1) 
Study screening will occur approximately 2 to 28 days before Day 1. For the purposes of this 
study, patients will be considered enrolled when they provide signed informed consent and 
have met eligibility criteria. Written informed consent will be provided before any 
study-related procedures are performed. At screening, patients will be assigned a patient 
identification number and then all patients will be identified by their unique study patient 
number throughout the study. 
The following will take place at Screening: 
• Obtain informed consent by the patient prior to any study-related procedures.  
• Assign patient identification number. 
• Record demographics. 
• Record medical/surgical history. 
• Record histopathology and grade of STS. 


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• Obtain archival tissue samples (or 10 unstained histology slides), if available (optional). 
This can be collected any time during the study. 
• Record prior and concomitant medications. 
• Measure vital signs (blood pressure, pulse [radial or brachial (to be measured over 
30 seconds if performed manually)], respiration rate and oral body temperature.  
• Perform a physical examination, including body weight and height. 
• Record ECOG performance status. 
• Obtain a 12-lead ECG (Section 11.4.2.3). 
• Perform echocardiography (Section 11.4.2.3).  
• Collect urine and fasting blood samples for clinical laboratory tests (hematology, serum 
chemistry and urinalysis, Section 11.4.2.3).  Calculate creatinine clearance using 
Cockcroft-Gault equation.  
• Females of childbearing potential will undergo a urine pregnancy test (per inclusion 
criteria [Section 9.2], negative results must be obtained prior to dosing with study drug).  
• Assess inclusion/exclusion criteria (Sections 9.2 and 9.3). 
• Document all measurable tumor lesions with CT or MRI. If scans are available within 28 
days of the first dose of NOX66 (Dose-Escalation Phase) or before Cycle 1 in Dose-
Expansion Cohort there is no need for additional scans.  
• Assess AEs and update medical history (Section 15.2.1). 
• Patients must indicate willingness to self-administer study drug rectally. Instructions will 
be provided and competency in self-administration of a suppository similar in size to 
NOX66 must be demonstrated at the study site. Alternatively, if a given patient is 
accompanied by a reliable and willing household member, that individual may be trained 
to administer study drug to the patient and will be required to demonstrate competency 
at the study site. 
 
Results of these screening evaluations will be used to determine the patient’s eligibility to 
receive study drug according to the inclusion and exclusion criteria (Sections 9.2 and 9.3, 
respectively). Eligible patients who are selected and wish to continue will be scheduled to 
return for baseline (Day 1) assessments. 
 
Patients who have given their informed consent, have completed all baseline evaluations, 
and have met all inclusion and no exclusion criteria (reconfirmed at baseline) will self-
administer a single dose of NOX66 rectally. 
11.6.2 TREATMENT PERIOD 
The approximately 19-week Treatment Period (18 weeks for Dose Expansion Cohort) 
includes approximately 27 scheduled clinic visits Day 1 [baseline], Day 7 of NOX66 
monotherapy (Dose Escalation part), Days 1 and 2 of Treatment Cycles 1 to 6 of combined 
NOX66 and doxorubicin as well as Days 9 and 16 of Cycle 1 and the other subsequent 5 
cycles. Scheduled follow-up assessments will occur at Months 6, 9, 12, 15, and 18 (End of 


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Study) from Cycle 1 Day 1. Additional follow-up visits may be conducted at any time during 
study participation per Investigator’s discretion based on the type and severity of any 
notable safety finding as well as evaluation of any doxorubicin-induced toxicity (i.e., 
myelosuppression) that can delay the next dose of doxorubicin or result in a dose reduction.   
 
There is a window of ±1 day around scheduled study visits on Day 7 of NOX66 monotherapy 
and Day 2 of Cycles 1 to 6. A ±1 day window may also be utilized in the event of scheduling 
conflicts due to public holidays. A 7-day window is acceptable for all other visits during the 
follow-up period (Months 6, 9, 12, 15 and 18).  
 
Telephone contact between the site staff and the patient is to be encouraged between 
study visits to assess compliance, tolerability of the study drug. Sufficient study drug for a 
7-day period will be dispensed to the patients.   
11.6.2.1  Monotherapy Period (Days 1 to 6) – Only for dose escalation  
Eligible patients who are enrolled and wish to continue will return to the study site in the 
morning on Day 1 and the following will take place: 
• Record changes in medical history including any changes in concomitant medications 
since screening (Section 10.4). 
• Measure vital signs (blood pressure, pulse [radial or brachial (to be measured over 
30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1). 
• Perform a physical examination (including weight; Section11.4.2.2). 
• Obtain a triplicate 12-lead ECG after 5 minutes of rest in the supine position at -0.75, 
- 0.5 and -0.25 hours prior to administration of NOX66.  
• Collect urine and fasting blood samples for clinical laboratory tests (Table 3). ANC should 
be > 1000/μL3 prior to study drug administration.  
• Collect blood samples for genetic mutations, levels of BNP, troponin I, cytokines, 
chemokines and immunoassays prior to NOX66 administration. (These samples can be 
collected during Screening, if needed, at the end of all Screening assessments)  
• Females of childbearing potential will undergo a urine pregnancy test (per inclusion 
criteria [Section 9.2, negative results must be obtained prior to dosing with study drug). 
A window of -1 day is acceptable. 
• Collect PK pre dose blood sample within 15 minutes prior to administration of NOX66. 
• Administer questionnaires BPI-SF, EORTC QLQ-C30 and EORTC QLQ-FA12. Assess and 
record AEs and update medical history (Section 16). 
• Review inclusion/exclusion criteria (Sections 9.2 and 9.3). 
 
Once eligibility is confirmed, the following will occur: 
• Instructions for self-administration of study drug will be reviewed with the patient 
and/or a household member who has agreed to administer NOX66.    


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• The individualized doses will be determined based on the cohort to which they are 
assigned.  The frequency of dosing will be BID or TID beginning on Day 1. 
• Patients will be given an adequate supply of study drug for 7 days administration.   
The study drug will be self-administered by the patient; the patient will then undergo the 
following assessments:  
• On Day 1, PK blood sampling at 1, 2, 3, 4, 6, 8, and 24 hours post first dose. The 24-hour 
sample may be taken at home or in the clinic on Day 2, prior to NOX66 administration. 
• On Day 1, record triplicate 12-lead ECG at 1, 2, 5, and 8 hours after the first dose of 
NOX66. As noted in Section 11.4.3, ECGs are to be taken prior to the blood sample 
collection. 
• On Day 1, assess and review TEAEs (Section 16). 
• On Day 1 dispense a diary to record times of drug administration for Days 2 to 7. 
• On Day 1, instruct patients to return to the study site at Day 7 with completed diary and 
not to take the morning dose of NOX66 on Day 7 at home. 
11.6.2.2 Days 7 and 8 (±1 day) Only for Dose Escalation 
• On Day 7, assess and review TEAEs (Section 16). 
• On Day 7, collect urine and fasting blood samples for clinical laboratory tests (Table 3). 
• On Day 7, perform a physical examination (including weight; Section 11.4.2.2). 
• On Day 7, administer questionnaires BPI-SF, EORTC QLQ-FA12 and Suppository 
Acceptance Questionnaire (SAQ). 
• On Day 7, review treatment log (diary) and assess dosing compliance. 
• On Day 7, review and record concomitant medications (Section 10.4). 
• On Day 7, collect blood samples for BNP, troponin 1, chemokines, cytokines and 
immunoassays prior to NOX66 administration.  
• On Day 7, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1) prior to NOX66 administration. 
• On Day 7, administer the morning dose of NOX66 in the clinic. 
• On Day 7, 12-lead ECGs will be performed in triplicate at -0.75, -0.5 and -0.25 hours prior 
to and at 1, 2, 5, and 8 hours post morning dose of NOX66. Holter monitoring will run 
from 8 to 24 hours post morning dose of NOX66. 
• On Day 7, PK blood sampling pre dose and at 1, 2, 3, 4, 6, and 8 hours post application.  
• On Day 8, PK blood sampling at 8 or 12 hours after the last dose of NOX66 on Day 7 for 
those on a TID or BID regimen, respectively. These samples may be obtained by a visiting 
healthcare professional at home or in the clinic. 
11.6.2.3 Days 9-12 (Rest Period) Only for Dose Escalation 
• Document measurable tumor lesions with CT or MRI (no need to repeat if the previous 
scan was within 28 days prior to Cycle 1 Day 1). 
• Assess and review TEAEs (Section 16). 
• Review and record concomitant medications (Section 10.4). 


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11.6.2.4 Cycle 1   
• On Day 1 collect blood for BNP and troponin 1 prior to administration of NOX66. 
• On Day 1, perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30 and EORTC QLQ-FA12. 
• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
minimum ANC of 1000/μL3. On Days 9 and 16, obtain hematology and clinical chemistry 
values to determine if any dose-reduction or delay in doxorubicin may be needed for the 
next dose. 
• Dose Expansion only: Females of childbearing potential will undergo a urine pregnancy 
test prior to dosing. A window of -1 day is acceptable. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1 administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7.  
• On Day 2, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate [to be measured over 60 
seconds], and body temperature [oral or aural]; prior to the dose of doxorubicin (Section 
11.4.2.1). 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66. 
• On Day 2, 12-lead ECGs will be performed in triplicate at -0.75, -0.5 and -0.25 hours prior 
to and at 1, 2, 5, and 8 hours post morning dose of NOX66. Holter monitoring will run 
from 8 to 24 hours post morning dose of NOX66. 
• On Day 2, PK samples are to be collected at within 15 minutes prior to NOX66 and at 1 
and 2 hours (Dose Escalation only) and at 4 and 6 hours (Dose Expansion Cohort) after 
NOX66 administration and assayed for idronoxil and metabolites. PK samples will also be 
obtained at 0.5, 4 and 6 hours after the end of the doxorubicin infusion and assayed for 
doxorubicin and doxorubicinol.  
• PK samples will be obtained within 15 minutes prior to the last morning dose of NOX66 
on Day 7 (Dose Escalation and Dose Expansion Cohorts). These samples can be collected 
at the patients’ home. 
• On Day 8 PK samples will be obtained at 8 or 12 hours after the last dose of NOX66 for 
those on a TID or BID, regimen, respectively (Dose Escalation Cohorts). These samples 
can be collected at the patients’ home or in the clinic. 
• Review and record concomitant medications (Section 10.4). 
• Assess and review TEAEs (Section 16). 
• On Day 1, for those patients in the Dose-Expansion Cohort, blood samples for genetic 
mutations, BNP, troponin I, cytokines, chemokines and immunoassays will be obtained 
prior to the first dose of NOX66, if not already collected at Screening. 
• Echocardiography should be repeated prior to the first dose of doxorubicin if, after the 
first screening echocardiograph, a patient has clinical symptoms that may indicate 
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11.6.2.5 Cycle 2 
• On Day 1 review treatment log, collect unused study drug, and assess compliance, from 
previous cycle. If needed, patients may be counseled to about being compliant with 
study drug. 
• On Day 1, perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12, and SAQ. 
. 
• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
minimum ANC of 1000/μL3. On Days 9 and 16, obtain hematology and clinical chemistry 
values to determine if any dose-reduction or delay in doxorubicin may be needed for the 
next dose. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1 administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7. 
• On Day 2, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate [to be measured over 60 
seconds], and body temperature [oral or aural]; prior to the dose of doxorubicin (Section 
11.4.2.1). 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66. 
• On Day 2, triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine 
position at -0.75, -0.5 and -0.25 hours prior to and at 1, 2, 5, and 8 hours post application 
of NOX66. 
• On Day 2, PK samples are to be collected within 15 minutes prior to the morning dose of 
NOX 66 administration (8or 12 hours after the last dose of NOX66 on Day 1) and at 4 
hours post NOX66 administration and will be assayed for idronoxil and metabolites.  
• On Day 2, PK samples are to be collected at 0.5 and 4 hours after the end of the 
doxorubicin infusion and assayed for doxorubicin and doxorubicinol. 
• Review and record concomitant medications (Section 10.4). 
• Assess and review TEAEs (Section 16).  
• On Day 21, assess tumor response by CT or MRI.  
11.6.2.6 Cycle 3  
• On Day 1 review treatment log, collect unused study drug, and assess compliance, from 
previous cycle. 
• On Day 1, perform echocardiography (Section 11.4.2.3). 
• On Day 1, collect blood for BNP, troponin 1, cytokines, chemokines and immunoassays 
prior to administration of NOX66. 
• On Day 1, perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12, and SAQ.  
• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
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values to determine if any dose-reduction or delay in doxorubicin may be needed for the 
next dose. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1 administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7. 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66.  
• Measure vital signs (blood pressure, pulse [radial or brachial (to be measured over 
30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1) prior to the dose of doxorubicin on Day 2. 
• On Day 2, triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine 
position at 0.25 hours prior to and at 1, 2, 5, and 8 hours post application of NOX66. 
• Review and record concomitant medications (Section 10.4). 
• On Day 2, PK samples are to be collected at 4 hours post NOX66 administration assayed 
for idronoxil and metabolites.  
• PK samples will be obtained just prior to the last morning dose on Day 7 (Dose-
Escalation and Expansion Cohorts) and on Day 8 at 8 or 12 hours after the last dose of 
NOX66 on Day 7 for those on a TID or BID regimens, respectively (Dose-Escalation 
Cohorts only). The Day 8 samples can be collected at home or in the clinic. 
• Assess and review TEAEs (Section 16). 
11.6.2.7 Cycle 4 
• On Day 1 review treatment log, collect unused study drug, assess compliance, from 
previous cycle. 
• On Day 1, perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12 and SAQ. 
• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
minimum ANC of 1000/μL3. On Days 9 and 16, obtain hematology and clinical chemistry 
values to determine if any dose-reduction or delay in doxorubicin may be needed for the 
next dose. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1 administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7. 
• On Day 2, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1) prior to the dose of doxorubicin. 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66. 
• On Day 2, triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine 
position at -0.25 hours prior to and at 1, 2, 5, and 8 hours post morning dose of NOX66. 
• On Day 2, PK samples are to be collected prior to the morning dose of NOX66 
administration (8 or 12 hours after the last dose of NOX66 on Day 1) and 4 hours post 
NOX66 administration and assayed for idronoxil and metabolites.  


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• On Day 2, PK samples are to be collected at 0.5 and 4 hours after the end of the 
doxorubicin infusion and assayed for doxorubicin and doxorubicinol. 
• Review and record concomitant medications (Section 10.4). 
• Assess and review TEAEs (Section 16). 
• On Day 21, assess tumor response by CT or MRI.  
11.6.2.8 Cycle 5 
• On Day 1 review treatment log, collect unused study drug, assess compliance, from 
previous cycle. 
• On Day 1, perform echocardiography (Section 11.4.2.3). 
• On Day 1 collect blood for BNP and troponin 1 prior to administration of NOX66. 
• On Day 1 perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12  and SAQ. 
• On Day 1, record ECOG status. 
• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
minimum ANC of 1000/μL3. On Days 9 and 16, obtain hematology and clinical chemistry 
values to determine if any dose-reduction or delay in doxorubicin may be needed for the 
next dose. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1, administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7. 
• On Day 2, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1) prior to the dose of doxorubicin. 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66. 
• On Day 2, triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine 
position at -0.75, -0.5 and -0.25 hours prior to and at 1, 2, 5, and 8 hours post morning 
dose of NOX66. 
• On Day 2, PK samples are to be collected at 4 hours post NOX66 administration assayed 
for idronoxil and metabolites.  
• PK samples will be obtained just prior to the last morning dose on Day 7 (all cohorts) and 
on Day 8 at 8 or 12 hours after the last dose of NOX66 on Day 7 for those on a TID or BID 
regimens, respectively (Dose-Escalation Cohorts). The Day 8 samples can be collected at 
home or in the clinic. 
• Review and record concomitant medications (Section 10.4). 
• Assess and review TEAEs (Section 16). 
11.6.2.9 Cycle 6 
• On Day 1 review treatment log, collect unused study drug, assess compliance, from 
previous cycle. 
• On Day 1, perform a physical examination (including weight, Section 11.4.2.2). 
• On Day 1 administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12, and SAQ. 


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• On Day 1, collect urine and fasting blood samples for clinical laboratory tests prior to the 
first dose of NOX66 (Table 3). Prior to the start of the cycle, the patient must have a 
minimum ANC of 1000/μL3. On Days 9 and 16, obtain hematology and clinical chemistry 
values. 
• On Day 1, dispense sufficient supply of study drug for 7 days administration.   
• On Day 1, administer the appropriate number of NOX66 suppositories/per day per 
assigned dose cohort and instruct the patient to take the appropriate number of 
suppositories on Days 2-7. 
• On Day 2, measure vital signs (blood pressure, pulse [radial or brachial (to be measured 
over 30 seconds if performed manually)], respiration rate and body temperature [oral or 
aural]; Section 11.4.2.1) prior to the dose of doxorubicin. 
• On Day 2, administer doxorubicin (75 mg/m2) over 15 minutes (or as per standard of 
care) at approximately 1 hour after administration of NOX66. 
• On Day 2, triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine 
position at- 0.25 hours prior to and at 1, 2, 5, and 8 hours post morning dose of NOX66. 
• On Day 2, PK samples are to be collected at pre-dose of NOX66 administration and at 4 
hours post NOX66 administration and assayed for idronoxil and metabolites.  
• On Day 2, PK samples are to be collected at 0.5 and 4 hours after the end of the 
doxorubicin infusion and assayed for doxorubicin and doxorubicinol. 
 
The following assessments are required at Cycle 6 Day 21, or at Early Termination if the 
patient discontinues the study during the treatment period: 
• Collect blood for BNP, troponin 1, immunoassays, cytokines, chemokines and genetic 
mutation,  
• Assess tumor response with CT or MRI. 
• Perform a physical examination (Section 11.4.2.2). 
• Measure vital signs (blood pressure, pulse [radial or brachial (to be measured over 30 
seconds if performed manually)], respiration rate [to be measured over 60 seconds], and 
body temperature [oral or aural] (Section 11.4.2.1). 
• Collect urine and fasting blood samples for clinical laboratory tests (Section 11.4.2.4).   
• Administer questionnaires BPI-SF, EORTC QLQ-C30, EORTC QLQ-FA12 and SAQ. 
• Perform echocardiography (Section 11.4.2.3). 
• Review treatment log, collect unused study drug, and assess compliance. 
• Review and record concomitant medications (Section 10.4). 
• Assess and review TEAEs (Section 16). 
11.6.2.10 
Months 6, 9 and 12 (from Cycle 1 Day 1) 
• Assess tumor response with CT or MRI. 
• Single 12-lead ECG will be obtained after 5 minutes of rest in the supine position.  
• Administer questionnaires BPI-SF, EORTC QLQ-C30 and EORTC QLQ-FA12. 
• Review and record concomitant medications. Restrictions on concomitant medications 
are to be removed compared to NOX66 monotherapy and Cycles 1 to 6. 
• Assess and review AEs (Section 16). 
• Assess overall survival. 


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11.6.2.11 
Months 15 (from Cycle 1 Day 1) 
• Conduct telephone follow-up or chart review. 
• Assess and review AEs.  
• Assess overall survival. 
11.6.2.12 
Month 18 (from Cycle 1 Day 1) - End of Study/Early Termination  
• Assess tumor response with CT or MRI, including patients who discontinue the study for 
progressive disease. 
• Measure vital signs (blood pressure, pulse [radial or brachial (to be measured over 30 
seconds if performed manually)], respiration rate and body temperature [oral or aural]; 
Section 11.4.2.1). 
• Assess ECOG performance status. 
• Collect urine and fasting blood samples for clinical laboratory tests (Section 11.4.2.4).   
• Administer questionnaires BPI-SF, EORTC QLQ-C30 and EORTC QLQ-FA12. 
• Perform a physical examination (Section 11.4.2.2). 
• Review and record concomitant medications.  
• Assess and review TEAEs (Section 16). 
• Assess overall survival. 


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Table 4 Schedule of Procedures and Assessments for Three Periods of the Study  
 
      Procedure/Assessment 
 
Study Day 
Dose Escalation & 
Dose Expansion 
Dose Escalation  
NOX66 Monotherapy Period 
Screening 
Monotherapy (Days) 
Off-treatment Days 
Day -28 to Day -1 
1 
2 
3 
4 
5 
6 
7 
8 
9-12 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical and surgical history1 (including 
histopathology data and STS grade) 
X 
X 
 
 
 
 
 
 
 
 
Assess disease status (CT and/or MRI)2 
X 
 
 
 
 
 
 
 
 
X 
Vital signs3 
X 
X 
 
 
 
 
 
X 
 
 
Physical examination4 
X 
X 
 
 
 
 
 
X 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
X 
 
 
Hematology, clinical chemistry5 
X 
X 
 
 
 
 
 
X 
 
 
Urine pregnancy test (WOCBP only) 
X 
X 
 
 
 
 
 
 
 
 
BNP, troponin I  
 
X 
 
 
 
 
 
X 
 
 
Blood for cytokines, chemokines, immunoassays 
(ENOX2) 
X ϯ 
X ϯ 
 
 
 
 
 
X 
 
 
Genetic mutation sample 
Xϯ 
X ϯ 
 
 
 
 
 
 
 
 
Archival tissue sample (Optional) 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
12-lead ECG6  
X 
X 
 
 
 
 
 
X 
 
 
Holter monitoring6 
 
 
 
 
 
 
 
X 
 
 
Dispense 7-day supply of NOX66 
 
X 
 
 
 
 
 
 
 
 
Echocardiography  
X 
 
 
 
 
 
 
 
 
 
Administer NOX667 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PK samples8 
 
X 
X 
 
 
 
 
X 
X 
 
Record AEs 
X 
X 
Prior & concomitant medications  
X 
X 
Assess dosing compliance9 
 
 
 
 
 
 
 
X 
 
 
Brief Pain Inventory (BPI-SF) 19 
 
X 
 
 
 
 
 
X 
 
 
EORTC QLQ-C3019 
 
X 
 
 
 
 
 
 
 
 
EORTC QLQ-FA1219  
 
X 
 
 
 
 
 
X 
 
 
Suppository Acceptance Questionnaire10, 19 
 
 
 
 
 
 
 
X 
 
 


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Dose Escalation and Dose Expansion  
Combination of Doxorubicin and NOX66 Treatment Period Cycles 1 - 3 
Procedure/Assessment  
                                                 Study Day 
Cycle 11 
Cycle 2 
Cycle 3 
1 
2 
3-7 
8 
9 & 16 
21 
1 
2 
3-7 
9 & 16 
21 
1 
2 
3-7 
8 
9 & 16 
21 
Assess disease status (CT and/or MRI)2 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Vital signs 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, clinical chemistry 
X 
 
 
 
X11 
 
X 
 
 
X11 
 
X 
 
 
 
X11 
 
Urine pregnancy test (WOCBP only) 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BNP, troponin I   
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood for cytokines, chemokines, 
immunoassays (ENOX2)  
X*, ϯ 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Genetic mutation sample 
X*, ϯ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
12-lead ECG6 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Holter monitoring6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
X18 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Dispense 7-day supply of NOX66 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Administer NOX6612 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Administer doxorubicin13 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
PK samples14 
 
X 
X 
X# 
 
 
 
X 
 
 
 
 
X 
X 
X# 
 
 
Record AEs16 
X 
Prior and concomitant medications  
X 
Collect unused medication, review 
patient log and assess compliance 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Brief Pain Inventory (BPI-SF)19 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
EORTC QLQ-C3019 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
EORTC QLQ-FA1219 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Suppository Acceptance 
Questionnaire10, 19 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Overall survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Dose Escalation and Dose Expansion 
Combination of Doxorubicin and NOX66 Treatment Period Cycles 4-6 
Procedure/Assessment  
                                                   Study Day 
Cycle 41 
Cycle 5 
Cycle 6 
1 
2 
3-7 
9 & 16 
21 
1 
2 
3-7 
8 
9 & 16 
21 
1 
2 
3-7 
9 & 16 
21/ET1
Assess disease status (CT and/or MRI)2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Physical examination 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
ECOG performance status 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Hematology, clinical chemistry 
X 
 
 
X11 
 
X 
 
 
 
X11 
 
X 
 
 
X 
X 
BNP, troponin I   
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Blood for cytokines, chemokines, 
immunoassays (ENOX2)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Genetic mutation sample  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECG6 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Holter monitoring6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 7-day supply of NOX66 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Echocardiography 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Administer NOX6612 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
Administer doxorubicin13 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PK samples14 
 
X 
 
 
 
 
X 
X 
X# 
 
 
 
X 
 
 
 
Record AEs16 
X 
Prior and concomitant medications  
X 
Collect unused medication review 
patient log and assess compliance 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 Brief Pain Inventory (BPI-SF) 19 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
EORTC QLQ-C3019 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
EORTC QLQ-FA1219  
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Suppository Acceptance10, 19 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Overall survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Abbreviations: BNP = brain type natriuretic peptide; CT = computed tomography; ECOG=Eastern Cooperative Oncology Group; ECG=electrocardiogram; ENOX2 = Ecto-NOX 
disulfide-thiol exchanger 2; EOS=End-of-Study; ET=Early Termination; Mo = month; MRI = magnetic resonance spectroscopy; PK=pharmacokinetics; QOL = Quality of Life; 
WOCBP = women of childbearing potential   
Note:  For days not specifically designated on the schedule of assessments, the standard of care for the individual institution will be followed, any AEs and concomitant 
medications will be recorded on the eCRF.   
ϯ Blood samples for chemokines, cytokines, immunoassays (ENOX2) and genetic mutation to be collected either after eligibility is confirmed at Screening, or on Day 1 just 
prior to the first dose of NOX66.  
# Dose Escalation Cohort only 
*Dose Expansion Cohort only 
 
 
 
 
 
 
 
 
 


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1. Full medical and surgical history will be recorded at Screening. At Day 1 monotherapy; an interim history is to be recorded prior to first dose of NOX66. 
2. Standard of care imaging performed prior to informed consent but within 28-days of enrollment may be used to confirm screening requirements. Disease status will be 
measured by radiologic methods (CT or MRI) at Screening, prior to beginning of Cycle 1 (only for dose escalation, if the previous scan is more than 28 days), end of Cycles 
2, 4 and 6, at Months 6, 9 and 12 and End of Study. No patient is permitted to start a subsequent cycle until it is confirmed that disease progression has not occurred at 
the scheduled imaging assessment timepoint.  
3. Vital signs will include weight, body temperature, respiratory rate, radial pulse rates, and systolic and diastolic blood pressures. Height and body surface area will be recorded 
at Screening only. 
 Dose Escalation and Dose Expansion 
Follow-Up Period and End of Study/Early Termination 
              
 
Assessment                                                          
Study Day 
Follow-Up (months from Cycle 1 Day 1) 
EOS/ET15 
6 
9 
12 
1517 
18 
Assess disease status (CT and/or MRI)2 
X 
X 
X 
 
X 
Vital signs 
 
 
 
 
X 
Physical examination 
 
 
 
 
X 
ECOG performance status 
 
 
 
 
X 
Hematology 
 
 
 
 
X 
Clinical chemistry 
 
 
 
 
X 
Urinalysis 
 
 
 
 
X 
12-lead ECG 
X 
X 
X 
 
 
Record AEs17 
X 
X 
X 
X 
X 
Prior and concomitant medications  
X 
X 
X 
X 
X 
Brief Pain Inventory (BPI-SF) 19 
X 
X 
X 
 
X 
EORTC QLQ-C3019 
X 
X 
X 
 
X 
EORTC QLQ-FA1219  
X 
X 
X 
 
X 
Overall survival 
X 
X 
X 
X 
X 


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4. Complete physical examinations will be conducted at Screening (Day -28 to Day -1), prior to the first dose of NOX66, at the start of each treatment cycle and at End of Study. 
Complete physical examinations will include examination of general appearance, skin, neck (including thyroid), eyes, nose, throat, heart, lungs, abdomen, lymph nodes, 
extremities, muscular skeletal and nervous system.  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. Physical examinations need to include the assessment of the perineal and anal region. 
5. Hematology and chemistry assessments will be done weekly during Cycle 1 and with a window of (±2 days) during Cycle 2-6 and End of Study/Early Termination.   
6. Refer to Table 8 for details. Triplicate 12-lead ECGs will be obtained after 5 minutes of rest in the supine position at -0.75, -0.5 and -0.25 hours prior to administration 
of NOX66 and at 1, 2, 5, and 8 hours after the NOX66 application on Monotherapy Days 1 and 7 (Dose Escalation patients only) and Cycle 1 Day 2 (all patients). Holter 
monitoring will be recorded from 8 to 24 hours post NOX66 on Monotherapy Day 7 and Cycle 1 Day 2.  On Day 2 of Cycles 2 to 6, triplicate 12-lead ECGs will be 
obtained after 5 minutes of rest in the supine position at -0.25 hours prior to and at 1, 2, 5 and 8 hours post morning dose of NOX66. 
7. Patients will receive instructions on how to use the suppository and receive an adequate number of dosage units for the assigned dose level. ANC must be > 1000/µL3 prior 
to NOX66 administration. 
8. In the NOX66 monotherapy, PK samples will be obtained on Day 1 at pre-dose (within 15 minutes of dosing) and at, 1, 2, 3, 4, 6, 8, and 24 hours post application. On Day 7, 
PK samples will be collected at pre-dose (within 15 minutes prior to dosing) and at 1, 2, 3, 4, 6, and 8 hours post application as well as on Day 1 of the Washout Period at 8, 
or 12 hours after the last dose of NOX66 for those on a TID or BID regimens, respectively.   
9. Dosing compliance for NOX66 will be assessed weekly. Days with an abnormally high number of bowel movements are to be noted in the eCRF. 
10. Suppository Acceptance Questionnaire will be used to assess how acceptable the dosage form is to the patient. 
11. The additional tests for hematology and serum chemistry on Days 9 and 16 are to assess any hematological or clinical laboratory tests for DLTs and/or require a dose reduction 
to 60 mg/m2 or lower (37.5 mg/m2 or 18.75 mg/m2 based on serum bilirubin), or a delay in initiation of another cycle of the combination. These additional hematological and 
clinical laboratory tests should be performed at each cycle. Visit windows are ± 2 days of the scheduled visit.  
12. During combination treatment cycles, NOX66 is administered on Days 1 to 7 and doxorubicin is administered on Day 2.   
13. Doxorubicin (75 mg/m2 or reduced dose) to be given on Day 2 of each 21-day cycle. 
14. For Dose-Escalation Cohorts, PK samples will be obtained at pre-dose and at 1 and 2 hours post NOX66 on Day 2 Cycle 1. PK samples for idronoxil will be obtained on Day 2 
of Cycles 2, 4 and 6 at pre-dose and 4 hours post dose.  Additional PK samples for idronoxil will also be obtained pre-dose on Day 7 and at 8 or 12 hours after the last dose of 
NOX66 on Day 7 for those on a TID or BID regimens, respectively on Cycles 1, 3, and 5. For the Dose Expansion Cohort, PK samples for idronoxil will be obtained on Day 2 of 
Cycles 1, 2, 4, and 6 at pre-dose and at 4 hours post NOX66 and on Cycle 1 at 6 hours post NOX66. On Cycles 1, 3, and 5 PK samples are to be collected just prior to the 
morning dose of NOX66 on Day 7. For doxorubicin in the Dose Escalation Cohort, PK samples will be obtained at 0.5, 4 and 6 hours after the end of infusion on Day 2 Cycle 1 
and at 0.5 and 4 hours at the end of infusion on Day 2, Cycles 2, 4 and 6. For doxorubicin in the Dose Expansion Cohort, PK samples will be obtained at 0.5, 4 and 6 hours 
after the end of infusion on Day 2 Cycle 1 and at 0.5 and 4 hours at the end of infusion on Day 2, Cycles 2, 4 and 6 (Table 7). 
15. All patients who discontinue the study early for whatever reason after the first dose of NOX66, or during treatment cycles (Cycles 1-6), will be followed up within 28 days of 
discontinuation and submit to assessments detailed in the column of Cycle 6 Day 21/Early Termination. Patients who discontinue the study early during the follow-up period 
will complete a final visit with assessments detailed in the column of End of Study/Early Termination. Patients who complete the study in full will have an End of Study visit 
at Month 18. 
16. Adverse events to be recorded up to 30 days after the last dose of NOX66 or doxorubicin, whichever is longer. 
17. Month 15 will be telephone follow-up/chart review. 
18. Echocardiography should be repeated prior to the first dose of doxorubicin if, after the first screening echocardiograph, a patient has clinical symptoms that may indicate 
worsening cardiac function. 
19. Study Questionnaires (EORTC QLQ-C30, EORTC QLQ-FA12, BPI-SF and SAQ) to be administered if available in the required language.  
 


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12 METHODS OF ASSIGNMENT OF INTERVENTION 
12.1 ALLOCATION OF TREATMENT 
The Investigator or designee will record key information on the patient in the eCRF to verify that 
the patient meets the inclusion/exclusion criteria (Sections 9.2and 9.3). The Investigator must 
not prescribe the study drug until the patient’s enrollment is approved and the patient has been 
assigned to a cohort and dose level based on what is needed to complete the cohort (3 or 6 
patients or more if there are discontinuations, or the dose group needs to be expanded for a 
particular reason). The Investigator will then dispense to the patient an adequate number of 
either the 400 or 600 mg suppository dosage forms to complete the NOX66 monotherapy 
portion of the study or a treatment cycle with doxorubicin. Each patient number will be used 
only once, in sequential order within a cohort as noted below.   
Cohort 1 
Patient Numbers 101-109 
Cohort 2 
Patient Numbers 201-209 
Cohort 3 
Patient Numbers 301-309 
The patient numbers for the Dose-Expansion Cohort will range from 401-424. 
12.2 BLINDING AND UNBLINDING 
This is an open label study.  
13 DATA COLLECTION AND MANAGEMENT 
13.1 METHODS 
The Investigator must ensure there will be primary source documentation for all patient data 
collected as part of the study, and the data will not be recorded directly on to the eCRFs 
without the availability of such primary documentation, except for cases in which the Sponsor 
has predetermined that direct data entry into specified pages of the patient’s eCRF is 
appropriate. The source data may include such documents as clinical notes, laboratory result 
sheets, pathology reports, radiology results, etc., and will be retained in each patient’s medical 
record or research chart. Electronic CRFs will be provided by the Sponsor. 
The Investigator will be responsible for the timeliness, completeness, and accuracy of the 
information entered on the eCRF. The Investigator will provide access to the Medical Monitor 
or designated Sponsor representative(s) for the periodic review of all study records, source 
documents among other records for review and inspection to assure accuracy and completeness 
of the eCRFs. All eCRFs will be 100% source verified against corresponding source 
documentation (e.g., office and clinical laboratory records) for each patient. 
The Sponsor and designated Sponsor representative(s) will maintain frequent contact with each 
site to assure the study is conducted according to the Protocol and that all data collected are 


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accurate and complete. Any deficiencies identified by the Sponsor or representative during the 
study will be communicated to the site for prompt correction. 
13.1.1 ELECTRONIC CASE REPORT FORM 
All information relative to the study will be recorded on an eCRF to be supplied to the 
Investigator. Instructions will be provided for the completion of the eCRF. Data corrections will 
be automatically documented via the electronic data capture (EDC) software’s “audit trail.” 
13.1.2 STORAGE OF DOCUMENTS 
The Investigator will retain source documents and all other study related documents for 2 years 
after the last approval of a marketing application in an International Council for Harmonization 
(ICH) region or at least 2 years after the formal discontinuation of the clinical development of 
the investigational product.  
13.2 DATA MANAGEMENT 
The Sponsor or a designee/CRO will supply eCRFs. An eCRF must be completed for each patient 
who signs an Informed Consent Form (ICF). All data collected during the study will be recorded 
in this individual, patient-specific eCRF. Instructions will be provided for the completion of the 
eCRF. and any corrections made will be automatically documented via the EDC software’s “audit 
trail” as described above. 
Completion of the eCRF should be kept current to enable the monitor to review the patient’s 
status throughout the course of the study. All information and other material to be used by 
patients and investigative staff must use vocabulary and language that are clearly understood.  
The eCRF will be completed, reviewed, and signed off or e-signed by the Investigator. The 
Investigator will sign and date the indicated places on the eCRF via the EDC system’s electronic 
signature. These signatures will indicate that the Investigator inspected or reviewed the data on 
the eCRF, the data queries, and the study site notifications, and agrees with the content. 
If a patient is assigned to receive NOX66 and is not treated with study drug, the reason must be 
recorded on the eCRF.  
13.2.1 DATA CODING 
Medications will be coded from the WHO Drug Dictionary and medical history and adverse 
events will be coded using the MedDRA (Version 22 or higher) terminology for System Organ 
Class and Preferred Term. 
13.2.2 DATA VALIDATION 
To ensure the quality of clinical data across all patients and study sites, a Clinical Data 
Management review will be performed on patient data according to specifications given to the 
CRO. Data will be vetted both electronically and manually for CRFs and the data will be 
electronically vetted by programmed data rules within the application. Queries generated by 
rules and raised by reviewers will be generated within the EDC application. During this review, 
patient data will be checked for consistency, completeness, and any apparent discrepancies.   


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Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
A Data Management Plan will be developed to describe all manual and electronic validation 
checks of the data prior to analysis. 
14 STATISTICAL SECTION 
14.1 SAMPLE SIZE 
Up to 18 patients may be enrolled in the Dose Escalation part of this study, in cohorts of 3 or 6 
patients at each specified dose. Patients must take at least 80% of their prescribed doses to be 
considered eligible for MTD evaluation. Sixteen patients will be enrolled in the Dose Expansion 
part of this study.   
These sample sizes are not based on statistical considerations but are deemed sufficient to 
determine the MTD for and to describe the pharmacokinetic characteristics of this agent.  
An expansion cohort of N=16 will allow a total sample size of up to 34 patients. If the expected 
response rate is 18% (6/34) for a hypothetical comparator and the expected response rate of 
NOX66 will be 24% (8/34) in the current NOX66-004 trial, this sample size ensures an 85% 
probability that the observed response rate of NOX66- will be greater than 18%. 
14.2 ANALYSIS SETS 
There will be two analysis sets 
• 
Safety Set:  All patients treated with at least one dose of idronoxil will be included in the 
Safety Set (SS). All analyses of safety, toxicity, and PK will be performed for this set. 
• 
Full Analysis Set:  All patients who complete at least one cycle of idronoxil + doxorubicin 
combination therapy will be included in the Full Analysis Set (FAS).  Analyses of efficacy, 
tolerability, and biomarkers will be performed for this set. 
14.3 STATISTICAL METHODOLOGY 
14.3.1 GENERAL STATISTICS METHODS 
All data will be summarized by idronoxil dose group. For safety analyses, a summary group 
consisting of all dose groups combined may also be presented. 
For all measurements, the baseline value will be the last measurement taken before the first 
dose of study drug, whether idronoxil or of idronoxil + doxorubicin depending on the cohort. 
Standard summary statistics will be presented for all measurements. For continuous variables, 
the standard summary statistics will be the number of observations (n), mean, standard 
deviation, median, minimum and maximum. For categorical variables, the standard summary 
statistics will be the number and percentage of observations in each category. Categories that 
are specified on the eCRF which contain no observations will be presented in the data 
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An AE with a completely missing start date will be assumed to start one minute after the date-
time of the first idronoxil dose. If the severity of a reported AE is missing, it will be assumed that 
the event is severe; similarly, if the relationship of a reported AE to study treatment is missing, 
it will be assumed that the event is definitely related to treatment. No other missing data will 
be imputed. Incomplete start dates for Adverse Events and Concomitant Medications and 
incomplete end dates for AEs will have missing parts imputed by a conservative procedure which 
will be specified in the Statistical Analysis Plan (SAP). 
14.3.2 DISPOSITION, DEMOGRAPHICS, AND BASELINE DISEASE CONDITION 
Patient disposition, baseline demographics, and baseline disease condition will be summarized. 
14.3.3 EXPOSURE TO TREATMENT 
The summary of exposure will include the final idronoxil and doxorubicin doses, and the 
cumulative doses of idronoxil and doxorubicin received over the course of the entire study.  
Summaries will also be provided of the number of idronoxil treatments missed, the number of 
changes in the idronoxil and doxorubicin doses, the number of patients receiving dexrazoxane, 
and the dexrazoxane dose. 
14.3.4 ADVERSE EVENTS 
An AE will be deemed treatment emergent (TEAE) if it starts or worsens in severity or toxicity 
after the beginning of treatment, whether with idronoxil or with idronoxil + doxorubicin. 
Adverse events will be coded using the MedDRA Dictionary, Version 22.0 (or higher). Treatment 
emergent adverse events will be summarized by MedDRA Preferred Term and System Organ 
Classification for each dose group. Separate summaries will be provided for TEAEs with onset 
prior to the first dose of doxorubicin, with onset during the first cycle of idronoxil+ doxorubicin 
therapy, and for TEAEs with onset after the end of the first treatment cycle. 
The toxicity of an AE will be assessed by the NCI-CTCAE, Version 5.0. Summaries of TEAEs will be 
provided by dose group and toxicity grade. Summaries of TEAEs will also be provided by dose 
group and Investigator-reported severity and by dose group and Investigator-reported 
relationship to study treatment. 
A summary will be provided of the overall incidence and the incidence of component terms for 
the Standardized MedDRA Queries (SMQs) for Cardiac Failure and for Cardiomyopathy. 
A separate summary will be provided of Serious Adverse Events (SAEs) by dose group.  
Summaries will be presented for all SAEs, for treatment-emergent SAEs, for treatment-
emergent SAEs that occur prior to the first dose of doxorubicin, during the first cycle of idronoxil 
+ doxorubicin combination treatment, and after the end of the first cycle of combination 
treatment. 
Deaths on study or within 30 days after a patient exits the study will be summarized by 
treatment. A listing of all deaths will be provided. 


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14.3.5 LABORATORY SUMMARIES 
Safety laboratory results will be summarized by dose group.  At each scheduled laboratory 
collection, the laboratory result and the change from baseline in laboratory result will be 
summarized for each laboratory parameter. CTC grades will be assigned to laboratory results 
where they are defined, and the frequency and percentage of each CTC grade will be included 
in the summary. 
Shift tables will be provided for change in CTC grade from baseline to end of study and from 
baseline to worst grade on study. 
Brain type natriuretic peptide measurements will be summarized using descriptive statistics at 
baseline and at Cycles 1, 3, 5, and the end of Cycle 6 or Early Termination (if occurs prior to the 
end of Cycle 6). The number and percentage of patients with BNP laboratory values greater than 
500 pg/mL and with BNP laboratory values between 100 and 500 pg/mL will be presented. 
Blood levels of chemokines and cytokines will be summarized using descriptive statistics at 
baseline, Day 7 of Monotherapy period (only for Dose Escalation), at Cycle 3, and at the end of 
Cycle 6 or at Early Termination (if occurs prior to the end of Cycle 6). 
Listings of genetic mutations at baseline and at end of Cycle 6 or Early Termination will be made.  
Blood levels of ENOX2 will be summarized using descriptive statistics at baseline, at Cycle 3, and 
at the end of Cycle 6 or at Early Termination (if occurs prior to the end of Cycle 6). These levels 
will also be assessed in the same manner for patients in the Dose Escalation Cohorts, including 
those on Day 7 of Monotherapy period, if the samples are collected.  
14.3.6 VITAL SIGNS 
Vital signs will be summarized by dose group. Descriptive statistics will be provided for each vital 
sign at each visit and for the change from baseline to that visit. For vital signs with an associated 
CTC grade, the summaries will include the number and percent of patients at each grade. 
14.3.7 ECG PARAMETERS 
For each ECG parameter (PR, RR, QRS, and QT intervals, and QT interval corrected for heart rate 
using QTcF intervals where the QT intervals corrected for heart rate by Fridericia’s formula [QTcF 
= QT/(RR)⅓], the parameter and the change from baseline in that parameter will be summarized 
at all time-points where an ECG is collected. Where triplicate ECG measurements are available, 
the descriptive statistics will be calculated using the arithmetic average of the three raw 
measurements. Holter monitoring will not assess ECG intervals but will provide information on 
cardiac rate and rhythms. 
14.3.8 OTHER SAFETY ANALYSES 
Echocardiography findings will be summarized by dose group at baseline and at Cycles 3, 5, and 
the end of Cycle 6 or Early Termination.  
Physical exam findings will be summarized by dose group at baseline, at the start of each cycle 
and at the End of Study or Early Termination. 


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ECOG performance status will be summarized at each visit where it is collected. 
14.3.9 PHARMACOKINETIC ANALYSES 
Blood concentration of idronoxil and metabolites will be summarized by collection time for each 
dose group using descriptive statistics. Separate summaries will be provided for idronoxil blood 
concentrations collected on Days 1 and 7 of idronoxil monotherapy, and from pre-dose to 4 
hours post dose on Day 2 of Cycles 1 to 6. Trough values will also be assessed on Days 7 and 8 
of Cycles 1, 3 and 5. Blood concentrations of idronoxil after monotherapy and in combination 
with doxorubicin will be compared. 
Plasma concentrations of doxorubicin and doxorubicinol will be summarized by collection time 
for each dose group using descriptive statistics.   
Pharmacokinetic parameters will be summarized by descriptive statistics for each dose group 
for idronoxil alone on Days 1 and 7. Graphical methods may be used to assess the relationship 
between idronoxil and doxorubicin concentrations and QTc values and other toxicities of 
interest. 
14.3.10 
 
EFFICACY ANALYSES 
Treatment response will be assessed by RECIST v1.1 criteria for patients in the FAS at the end of 
Cycles 2, 4, and 6, at the 6-month, 9-month, and 12-month follow-up visits, and at the End of 
Study or Early Termination. Along with CR, PR and SD, the ORR will be defined as the relative 
frequency of patients with either CR or PR, and the DCR will be defined as the relative frequency 
of patients with CR, PR, or SD. 
The ORR, the DCR, and the frequencies of CR, PR, SD, and PD will be summarized at the end of 
Cycles 2, 4 and 6 and at the 6-month, 9-month, 12-month and up to 18-month follow-up visits. 
A summary will also be provided of best response on study. 
At the assessment at the end of Cycle 6, a one-sided exact binomial test will be used to test the 
null hypothesis that the ORR is no greater than 0.20 (20%) against the alternative hypothesis 
that the ORR is greater than 0.20 at an approximate level p = 0.025. A similar test against the 
performance level of 0.20 will be performed for the rate of best objective response on study. 
Overall survival will be defined as the time in months from initial treatment until death or 
censoring. Patients not known to have died at the time of analysis will be censored at the time 
of last contact with study personnel., including patients who are lost to follow-up. The overall 
survival curve will be estimated for the FAS by the Kaplan-Meier method. 
Progression-free survival will be defined as the time in months from initial treatment until death, 
disease progression, or censoring.  Patients who are lost to follow-up will be censored at the 
time of their last contact with study personnel. Patients who leave the study to begin an 
alternative therapy will be censored on their day of study discontinuation. The PFS curve will be 
estimated for the FAS by the Kaplan-Meier method. 


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14.3.11 
 
QUALITY OF LIFE 
All Quality of Life (QoL) analyses will be performed on the FAS. Scales from the EORTC-QLQ-
C30and items from the Brief Pain Inventory – Short Form, EORTC-QLQ-FA12and Suppository 
Acceptance Questionnaire at each time point and changes from baseline will be summarized 
using descriptive statistics. Details of the scoring algorithms used to generate the QoL scores will 
be described in the SAP. 
A Statistical Analysis Plan (SAP) will be developed and the analysis will be performed by a 
statistician using SAS {version TBD}. 
14.3.12 
 
STATISTICAL ANALYSIS PLAN 
Further details on statistical methods, presentations, and rules for data handling will be 
provided in a Statistical Analysis Plan that shall be approved prior to the opening of the Dose 
Expansion Cohort. 
14.4 INTERIM AND ADDITIONAL ANALYSIS 
An interim analysis will be performed after all patients in the Dose Escalation cohorts have either 
discontinued or completed 3 treatment cycles, whichever comes first. A second interim analysis 
may also be performed after 50% of the patients in the Dose Expansion Cohort have either 
discontinued or completed 3 treatment cycles.  
The results from these analyses will not be used to modify the study design or to stop the study. 
15 MONITORING 
15.1 MONITORING OF CASE REPORT FORMS 
The study will be monitored by a CRO on behalf of the Sponsor. Monitoring will be conducted 
according to ICH GCP guidelines and Monitoring CRO SOPs. An initiation meeting will be 
conducted by CRO. At this meeting the protocol, the procedure for completing the eCRFs, and 
pertinent aspects of the eCRFs will be reviewed with the Investigator and all study staff. 
The Monitor will visit the Investigator at regular intervals to review the progress and conduct of 
the study. The CRFs will be checked for completeness and accuracy against the patient records, 
patient charts, laboratory reports, X-ray reports and scans as specified in the monitoring plan. 
Anonymity of the patient will be maintained at all times.  
Regulatory authorities, the IRB or the Sponsor may request access to patient clinical notes and 
other relevant study documentation for an on-site audit or inspection. The Investigator is 
obliged to facilitate this process by allowing full access. 
15.2 SAFETY DATA MONITORING 
The Medical Monitor will review and evaluate all toxicities causally associated with NOX66 alone 
in combination with doxorubicin in each cohort.   


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15.2.1 SAFETY MONITORING AND OVERSIGHT  
After each cohort has completed Cycle 1, the SRC meeting will be held. The meetings will be 
comprised of the enrolling Investigators, a representative from the Sponsor,  and may also 
include a cardiologist or other outside consultants at the Sponsor’s discretion. The role is to 
assess any DLTs and adjudicate the MTD and whether the study should continue or be 
terminated based on efficacy, safety and tolerability data. A charter for the SRC will be 
developed prior to initiation of the clinical study. 
If available, PK, PD, and efficacy data will also be included for review at the SRC meeting   
15.2.1.1 AE Reporting 
All AEs are graded according to NCI-CTCAE v5.0. AEs are captured from the time of consent and 
must be reported in the eCRF.  
. Some events may make the patient ineligible for enrollment. Unanticipated events should be 
reported to the IRB, according to its requirements. Patients will be questioned at every visit after 
the first dose until the last follow-up visit regarding the occurrence and nature of any TEAEs. All 
TEAEs will be reported, whether or not they are deemed to be related to investigational product. 
A description of the event or diagnosis including dates, severity, relationship to the 
investigational product, action taken and outcome, and whether or not the event was also 
serious, must be reported on the AE eCRF for each TEAE recorded in the patient’s chart. 
15.2.1.2 Expedited Reporting of Adverse Events  
The Medical Monitor should evaluate every AE to determine if (1) the AE meets the 
requirements for expedited reporting and/or (2) if the AE meets the criteria for a safety 
pause/prompt AE review (Section 15.2.2). The Medical Monitor’s contact information is 
provided in Section 16.2.  
The study product for which expedited reporting is required is NOX66. 
The Sponsor, or if designated, the CRO, will report all serious, unexpected, suspected adverse 
reactions observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND Safety 
Reports). SAE reporting procedures are provided in Section 16.1.2. 
15.2.2 SAFETY REVIEWS 
15.2.2.1 Initial Safety Evaluation 
Enrollment will be stepwise starting with Cohort 1 (N=3). After 3 patients complete Cycle 1 and 
have taken at least 80% of the target number of doses, and completed all safety evaluations, all 
data will be reviewed by the SRC to determine if the next cohort can be enrolled.  If no DLT was 
observed in a cohort of 3 patients, the next cohort of 3 new patients may be enrolled at the next 
higher dose level. 
15.2.2.2 Safety Considerations for Dose Escalation 
In addition to monitoring patient’s safety throughout the study period, the Medical Monitor and 
Investigator will participate in the SRC meeting to assess cumulative safety data available on all 


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patients who had received at least 80% doses to determine whether dose escalation may occur 
according the prespecified rules in Section 8.1.1 
15.2.2.3 Safety Pause and Prompt AE Review 
If a DLT occurs in 1 patient in a cohort of 3 patients at a given dose level of NOX66 + doxorubicin, 
then 3 more patients should be enrolled at that same dose level. If a DLT is not observed in the 
additional 3 patients, the next cohort of 3 new patients may be enrolled at the next higher dose 
level. 
If DLT occurs in 2 patients in a cohort of 6 patients at a given dose level, then this dose level will 
be defined as the DLT dose level. All Investigators will be informed, no additional patient(s) will 
be enrolled at the DLT dose level, and dose-escalation will stop. No more than 6 patients should 
be enrolled at the DLT dose level. 
The dose for the next cohort will be determined at the SRC review meeting to evaluate all the 
available safety (including AEs that are not DLTs).  
When a DLT occurs, the site must immediately inform the CRO who will then inform the other 
sites that a DLT has occurred and evaluate if a second DLT has occurred at any other sites. If 2 
or more DLTs occur at the same dose level, further enrollment of new patients at that dose level 
or higher across all sites will be suspended until the SRC meeting occurs to evaluate if the MTD 
has been exceeded. To be included in a dose-escalation decision or determination of MTD, an 
evaluable patient is defined as one who either experienced a DLT during the first 21-day 
treatment cycle (Cycle 1) or has not experienced a DLT and has taken at least 80% of the 
prescribed daily doses of NOX66 of the monotherapy period and the first 21-day treatment cycle 
and completed all safety evaluations required in Cycle 1.  
Due to the potential for Cycle 1 discontinuations, patients withdrawing for reasons other than 
safety will be replaced.  
When a dose escalation is stopped, the patients treated at lower doses can continue as planned. 
15.3 AUDITING 
Quality assurance (QA) procedures are designed to ensure complete, timely, and accurate 
submission of data, and that protocol requirements and complications and/or adverse events 
are immediately identified.  
In addition to the monitoring visits outlined above, an investigational site may undergo a QA 
audit. Noxopharm or their authorized representatives or a regulatory agency such as the FDA 
may conduct the audit. If the FDA requests an audit of the study site, the Investigator is required 
to inform Noxopharm or the monitoring CRO immediately. 


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16 ADVERSE EVENT REPORTING 
16.1 DEFINITIONS 
16.1.1 ADVERSE EVENTS 
An AE is any unanticipated or unintended medical occurrence or worsening of a sign or symptom 
(including an abnormal laboratory finding) or disease in a study participant, that occurs after the 
informed consent is obtained, which does not necessarily have a causal relationship with the 
study condition, procedures or study agent(s). An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational study product/procedure(s), whether or not related 
to the investigational study product/procedure(s).  
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition (including the physical examination), or abnormal results of diagnostic 
procedures (including laboratory test abnormalities).  
Events should also be considered AEs if they: 
• result in discontinuation from the study, 
• require treatment or any other therapeutic intervention, 
• require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality),  
• are associated with clinical signs or symptoms judged by the Investigator to have a 
significant clinical impact 
Clinically Significant Laboratory Changes: It is the Investigator’s responsibility to review the 
results of all laboratory tests as they become available. For each abnormal result, the 
Investigator needs to ascertain whether the abnormality presents a clinically significant change 
from baseline. If the change is due to the expected course of the patient’s underlying disease 
(e.g. elevated cholesterol in a study of dyslipidemia), it is not considered an adverse event unless 
the abnormality is more severe than expected. A laboratory test may be confirmed by repeat 
testing or other diagnostic tests before being considered an adverse event. If the laboratory 
abnormality is a significant change from baseline for the patient, then it should be considered 
an adverse event.  
An Adverse Event is not: 
• a surgical procedure 
• a situation where an untoward event did not occur, (e.g. an elective hospitalization) 
• the disease being studied, unless progression is more severe than anticipated 
• lack of efficacy 
• baseline conditions that have not worsened in severity or frequency 
• the puncture from venipunctures 
Pre-existing conditions or illnesses which are expected to exacerbate or worsen are not 
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All adverse events are to be followed up for 30 days post the last dose of study drug or until 
resolution (whichever is sooner).  
Adverse events reported by the patient or observed by the Investigator will be listed individually 
on an adverse event form in the eCRF. The signs and symptoms, time of onset, criteria for 
assessing causality to study drug (Table 5) and outcome categories should be defined (Table 6).In 
order to classify AEs and diseases, preferred terms and system organ classes will be assigned by 
the Sponsor to the original terms entered on the eCRF using the Medical Dictionary for 
Regulatory Activities (MedDRA) (Section 13.2.1). 
16.1.2 SERIOUS ADVERSE EVENTS 
The definitions of SAEs are given below. The Investigator is responsible for ensuring that all staff 
involved in the trial are familiar with the content of this section. 
A SAE or reaction is defined as any untoward medical occurrence that results in any of the 
following outcomes:  
• Death 
• Life-threatening adverse drug experience defined as any adverse drug experience that, 
in the opinion of the Investigator, places the patient at immediate risk of death from the 
reaction as it occurred. It does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• An in-patient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity, defined as “A substantial disruption of a 
person’s ability to conduct normal life functions” 
• Congenital anomaly/birth defect (in the offspring of a patient) 
The definition of SAE also includes any important medical event. Medical and scientific judgment 
should be exercised in deciding whether expedited reporting is appropriate in other situations, 
such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the previous definition. These should also usually be 
considered serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. Progression of malignancy 
(including fatal outcomes), if documented by the use of an appropriate method (for example, as 
per RECIST v1.1 criteria for solid tumors), should not be reported as an SAE and must be 
approved by the Sponsor. 
Treatment within or admission to the following facilities does not meet the criteria of ’in-patient 
hospitalization’ (although if any other SAE criteria are met, the event must still be treated as an 
SAE and immediately reported): 
• Emergency Department or Emergency Room  
• Outpatient or same-day surgery units 


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• Observation or short-stay unit  
• Rehabilitation facility  
• Hospice or skilled nursing facility  
• Nursing homes, custodial care or respite care facility  
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the trial), does not require reporting as a SAE to the Medical Monitor 
and Sponsor. 
The definition of ’related’ is that there is a reasonable possibility that the drug caused any of the 
adverse events described in Table 5. 
16.1.3 GUIDELINES FOR DETERMINING CAUSALITY AND SEVERITY 
The Investigator must assign a relationship of each adverse event to the receipt of the 
investigational product (NOX66 or the combination of NOX66 and doxorubicin). The Investigator 
will use clinical judgment to assess a plausible biologic mechanism for a temporal relationship 
between the onset of the event in relation to receipt of the investigational product, and the 
Investigator may determine possible alternate etiologies including underlying disease, 
concurrent illness or concomitant medications. The following guidelines should be used by 
Investigators to assess the relationship of an adverse event to study product administration.  
The criteria used for determining the relationship between the study drug/s and the Adverse 
Event are shown below. 
Table 5 
Relationship to Study Drug  
Unlikely/unrelated 
An AE with a temporal relationship to drug administration, which makes 
a causal relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations.  
Possible 
An AE with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
Likely 
An AE with a reasonable time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on 
withdrawal (rechallenge). Rechallenge information is not required to 
fulfil this definition. 
Certain 
An AE occurring in a plausible time relationship to drug administration 
and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drugs should be clinically 
plausible. The event must be definitive pharmacologically or 
phenomenologically using a satisfactory rechallenge procedure if 
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Hospitalization for elective surgery related to a pre-existing condition, routine clinical 
procedures, or social reasons that did not increase in severity or frequency after beginning the 
study are not considered to be AEs but must be recorded in the source documents. If the 
hospitalization is due to a pre-existing condition or was planned prior to the start of the study, 
the condition that led to the hospitalization should be recorded in the eCRF Medical History 
form. If the hospitalization arises from a pre-existing condition that did not worsen and the 
hospitalization was planned after the start of the study, the condition that led to hospitalization 
should be recorded in the AE page of the eCRF. In both cases, the condition that led to 
hospitalization should be recorded, and the relationship to study drug will be recorded as 
“Unrelated.” 
16.1.4 ACTION TAKEN AND OUTCOME 
The Action Taken with NOX66 and doxorubicin for every AE will be reported as either “Dose Not 
Changed”, “Dose Reduced”, “Dose Withdrawn” or “Dose Delayed”.  The Outcome of each AE 
will be entered as either: Resolved, Resolved with Sequelae, Ongoing, Death, or Unknown as 
noted in Table 6. 
Table 6 
Adverse Event Outcome Category 
‘Resolved’  
The patient has fully recovered from the adverse event with 
no residual effects observable. 
‘Resolved with Sequelae’  The patient has recovered from the adverse event, however 
there are residual effects observable. 
‘Ongoing’  
The adverse event is still present and observable. 
 ‘Death’  
The patient died as a result of the adverse event. 
‘Unknown’  
The outcome of the adverse is unknown at the time of report. 
16.2 RESPONSIBILITIES FOR REPORTING 
Investigators and the Sponsor are required by regulatory agencies worldwide to report adverse 
events which involve patients being administered a pharmaceutical product.  
All serious adverse events (SAE) occurring from the signing of informed consent until 30 calendar 
days after last study treatment, whether related to drug or not, must be reported to the Medical 
Monitor and appropriate Sponsor contact person within 24 hours of first knowledge of the 
experience using the appropriate study SAE Report Form. SAEs are to be followed until 
resolution or stabilization (with autopsy report if applicable). 
Deaths and other SAEs occurring > 30 calendar days after last study treatment that are deemed 
‘possibly’ or ‘probably’ related to the study treatment must be reported as SAEs on the SAE 
Report Form within 1 day of first knowledge of the event by the treating physician or research 
personnel (with an autopsy report if available). 
Deaths occurring > 30 calendar days after study trial treatment and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the 
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16.2.1 SAE AND UNRESOLVED AE FOLLOW-UP 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Medical Monitor as soon as possible using the SAE Report Form. The 
patient should be followed until it is determined that the event resolved, stabilized, or in the 
opinion of the Investigator the event is not going to improve due to underlying disease, or the 
patient dies or is lost to follow-up. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
The detailed SAE reporting process will be provided to the sites. 
16.2.2 INVESTIGATOR REPORTING OF AEs/SAEs/DEATHS AFTER STUDY DISCONTINUATION 
Thirty days after completing protocol-specific treatment or study discontinuation, treatment 
related AEs, SAEs, or deaths determined by the Investigator as treatment related are to be 
reported directly to the Sponsor. 
At the last scheduled study visit, the Investigator should instruct the patient to report to the 
Investigator any subsequent SAEs that the patient or the patient’s personal physician believes 
could be related to prior study treatment. 
The Sponsor should be notified if the Investigator becomes aware of the development of a new 
primary cancer or of a congenital anomaly in a subsequently conceived offspring of a patient 
who participated in the study. 
SAEs after study discontinuation considered related to study treatment are to be sent to the 
Sponsor. 
16.2.3 SPONSOR SAE REPORTING REQUIREMENTS 
The Sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Conference on Harmonization (ICH) guidelines, and/or local regulatory 
requirements. 
The Sponsor is responsible for reporting unexpected fatal or life-threatening events associated 
with the use of the trial drugs to the regulatory agencies and competent authorities via 
telephone or fax within 7 calendar days after being notified of the event. The Sponsor will report 
all related but unexpected SAEs including non-death/non-life-threatening related but 
unexpected SAEs associated with the use of the trial medications to the appropriate competent 
authorities (according to local guidelines), Investigators, and relevant IRB by a written safety 
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17 CONDUCT OF STUDY 
17.1 HUMAN RESEARCH  
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP (Committee 
for medicinal products for human use/ICH/135/95), and applicable regulatory requirements 
including the following: 
• 
European Commission Directive (2001/20/EC Apr 2001) 
• 
European Commission Directive (2005/28/EC Apr 2005) 
• 
United States Food and Drug Administration GCP Regulations: CFR Title 21, parts 11, 50, 
54, 56, and 312 as appropriate   
• 
The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics No. 1 of 25 
November 2014 and/or 
• 
Other applicable local regulations 
The Protocol and all other relevant study documents (informed consent, advertising etc.) will be 
submitted to the appropriate IRB for approval. Written confirmation of approval (noting 
version/ date of all approved documents) must be received from the Investigator before the 
study commences and approval of all documents pertaining to this study will be kept in the 
Study Master File. 
The IRB will have at all times the right to review all source documentation. 
17.2 SUBJECT CONFIDENTIALITY 
The Investigators and the Sponsor will preserve the confidentiality of all patients taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the patient’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or the CRO, patients should be identified by a unique 
patient identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (e.g., signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution permit 
authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the patient’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the patient that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the patient. 
17.3 REGULATORY APPROVAL 
The study protocol, patient information and consent form, the IB, any patient written 
instructions to be given to the patient, available safety information, patient recruitment 


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procedures (e.g., advertisements), information about payments and compensation available to 
the patients, and documentation evidencing the Investigator’s qualifications should be 
submitted to the IRB for ethical review and approval according to local regulations, prior to the 
study initiation. The written approval should identify all documents reviewed by name and 
version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator and/or Sponsor must submit and, where necessary, obtain approval from the 
IRB for all subsequent protocol amendments and changes to the ICF. The Investigator should 
notify the IRB of deviations from the protocol or SAEs occurring at the study site and other AE 
reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s Regulatory Affairs group or representative to 
whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation. If changes 
to the initial protocol and other relevant study documents are made, this representative will 
also ensure that any revised documents required for submission are submitted to regulatory 
authorities and implementation of these changes happen only after approval by the relevant 
regulatory bodies, as required. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Regulatory Authority in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 
17.4 GOOD CLINICAL PRACTICE 
The study will be conducted in accordance with the principles of Good Clinical Practice (GCP) 
using the guidelines established in 1996 by the International Conference on Harmonisation 
(ICH).  
Compliance with these guidelines ensures compliance with the currently approved version of 
the Declaration of Helsinki (October 2000) with notes of Clarification in 2002 (Washington) and 
2004 (Tokyo) and the Australian National Health and Medical Research Council Statement on 
Human Experimentation (2007) and any local legal and regulatory requirements. 
The CRO monitor and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the study (e.g., CRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH Good Clinical Practice (GCP) and local regulations on the conduct of 


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clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely. The frequency of the monitoring visit will vary based on the 
activity at each site. The monitor is responsible for inspecting the CRFs and ensuring 
completeness of the study essential documents. The monitor should have access to patient 
medical records and other study related records needed to verify the entries on the CRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be selected for 
audit by representatives from the Sponsor. Audit of site facilities (e.g., pharmacy, drug storage 
areas, laboratories) and review of study related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
The Investigator should respond to audit findings. In the event that a regulatory authority 
informs the Investigator that it intends to conduct an inspection, the Sponsor shall be notified 
immediately. 
17.5 ADHERENCE TO PROTOCOL 
No changes or deviations in the conduct of this protocol will be permitted, with the exception 
of emergency situations. If an emergency situation occurs the Investigator should contact the 
Sponsor by telephone as soon as possible. The nature and reasons for the Protocol deviation 
should be recorded in the CRF.  
In the event of an emergency, the Investigators will institute any medical procedures deemed 
appropriate. However, all such procedures must be promptly reported to the Sponsor, the 
Medical Monitor, and the IRB. 
Notify the IRB of all changes in the Protocol and provide documented approval of any change or 
deviation that may increase risk to the patient, and/or that may adversely affect the rights of 
the patient or validity of the investigation. 
17.5.1 PROTOCOL VIOLATION AND REPORTING 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority, and which was given approval/favorable 
opinion by the IRB. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the patient. Protocol 
violations are defined as any deviation from this protocol, and include items such as a study 
required evaluation not completed according to the protocol, a study visit completed outside of 


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the defined visit window, etc. A major protocol violation would include, but not be limited to, 
the following: 
• 
enrolment of a patient who does not meet the inclusion/exclusion criteria.  
• 
enrolment of a patient who has not provided informed consent.  
• 
the non-reporting of SAEs according to the procedure described in Section 16. 
All protocol violations will be reported to the Sponsor via a protocol violation form. Major 
protocol violations must be reported to the Sponsor as soon as the Investigator or the Data 
Monitor becomes aware of them.  
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a patient was ineligible or received the incorrect dose or study treatment, and had at least one 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB of deviations from the protocol in accordance 
with local procedures.   
17.6 SUPPLY OF NEW INFORMATION AFFECTING THE CONDUCT OF THE 
STUDY 
When new information becomes available that may adversely affect the safety of patients or 
the conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
IRB, and regulatory authorities of such information, and when needed, will amend the protocol 
and/or patient information. 
The Investigator should immediately inform the patient whenever new information becomes 
available that may be relevant to the patient’s consent or may influence the patient’s willingness 
to continue participation in the study. The communication should be documented on medical 
records, for example, and it should be confirmed whether the patient is willing to remain in the 
study.  
If the patient information is revised, it must be re-approved by the IRB. The Investigator should 
obtain written informed consent to continue participation with the revised written information 
even if patients were already informed of the relevant information. The Investigator or other 
responsible personnel who provided explanations and the patient should sign and date the 
revised ICF. 
17.7 PROTOCOL AMENDMENTS 
All changes to the protocol (modifications (e.g., changes to eligibility criteria, outcomes, 
analyses) must be documented by amendments, or administrative changes where applicable, 
and the amended protocol must be signed by Noxopharm and the Investigators. The amended 
protocol and a revised IC form, if necessary, will be submitted to each IRB for approval.  If the 
protocol modifications affect the CRFs, they will also be revised and provided to the sites. 
 
 


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18 SUBJECT INFORMED CONSENT 
The Investigator, or a person designated by the Investigator, is responsible to explain the nature 
of the study and the risks and benefits of taking part to the patient in order to obtain the 
patient's written consent. The patient and the person who conducted the informed consent 
discussion are to sign and personally date the consent form. 
It should be stressed that participation is voluntary. The patient can refuse to participate and is 
free to withdraw from the study at any time, without affecting their future medical 
management.  
Prior to undertaking any study specific activity, the Investigator should explain the nature of the 
study to the patient, including providing a written information sheet which should be read and 
retained by the patient. All patients must give fully informed consent, which must be obtained 
in writing by a personally dated signature and witnessed. The signed consent form should be 
available to be viewed by the Clinical Study Monitor and a copy of all consent documents 
provided to the patient. 
Patients must be informed that representatives of the Sponsor, IRB and regulatory authorities 
may inspect their medical records in order to verify the accuracy and authenticity of study 
documentation including information entered in the eCRF. Patients must be informed as to the 
nature of the privacy guidelines in place to protect their anonymity. 
19 DISCLOSURE OF DATA 
19.1 CONFIDENTIAL INFORMATION 
Patient medical information obtained during the study is confidential and disclosure to third 
parties other than those noted below is prohibited. All patients will be assigned a study 
identification number. Patients will be identified on eCRFs only by their patient number and 
initials. 
At the patient’s request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection on request by representatives of 
state and federal health authorities, the Sponsor, and the IRB. 
All published information from this study will be presented in such a way that it does not permit 
identification of individual patients. Patient identity will remain protected except as required by 
regulatory or legal inquiries. 
To fully evaluate patient safety issues that may arise during the study, Sponsor, or state and 
federal authorities will require direct access to source documents including trial-related 
monitoring, audits, IRB review and regulatory inspection(s). 


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It must be explained to the patient before enrollment into the study that the patient’s Protected 
Health Information obtained during the study may be shared with the study, Sponsor, state and 
federal authorities, and HREC regulatory inspections(s). 
19.1.1 STUDY RECORDS AND SOURCE DOCUMENTS 
All clinical information obtained by the Investigator is confidential, including that supplied by 
the Sponsor, and disclosure to third parties must be limited to: 
i. 
Those undertaking legitimate peer review of the scientific and ethical aspects of the 
study such as, but not limited to, the TGA and/or FDA. 
ii. 
Other staff participating in the study, so that necessary medical care can be undertaken. 
iii. 
The patients, so that written informed consent can be obtained. 
iv. 
Representatives of the Sponsor, including the Monitor(s). 
Patients will be identified to the Sponsor and regulatory authorities only by their study number 
and initials recorded on the CRF. Other patient details are to be obscured if a document is being 
forwarded to the Sponsor with the CRF or provided to regulatory authorities for review. 
The Investigator will maintain a patient enrolment log (patient numbers and the corresponding 
patient names) to enable the records to be identified. 
19.1.2 PRIOR TO STUDY COMMENCEMENT 
Prior to the release of clinical study supplies and the study commences, the following documents 
must be provided: 
i. An up-to-date, signed and dated Curriculum Vitae for all Investigators and relevant study 
staff. 
ii. The signed Protocol and any Amendments. 
iii. The signed clinical study agreement. 
iv. The signed letter from the IRB giving approval for the study (version numbers/dates of all 
approved documents to be included), together with a letter of constitution of the IRB. 
Copies of any other correspondence with the IRB relevant to the study should also be 
supplied. 
v. Current laboratory certification of the laboratories performing analysis, as well as current 
normal laboratory ranges for all laboratory tests. 
The Investigator shall provide to the Sponsor all observations and test results required in the 
Protocol and indicated in the CRFs. In particular all details of adverse events, as defined in the 
Protocol should be supplied. 
19.1.3 DOCUMENT RETENTION 
The Investigator at each site will retain copies (electronic form that has been backed up to a 
server) of the following documents in a secure place for a period of at least 2 years after the last 
approval of a marketing application in an ICH region or at least 2 years after the formal 
discontinuation of the clinical development of the investigational product. These documents 
may be retained for a longer period by agreement with the Sponsor. 


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i. A signed copy of the Protocol and any Amendments. 
ii. Copies of the patients' Case Report Forms and Data Clarification Forms. 
iii. The patient informed consent documents. 
iv. Copies of the Curricula Vitae of the Investigator and study staff. 
v. Copies of all correspondence with the IRB and FDA or other regulatory agencies. 
vi. Copies of relevant laboratory ranges. 
vii. Copies of all correspondence to and from the Sponsor and the Monitor and the 
Investigator. 
viii. The patient's original clinical notes. 
The Sponsor will provide the Investigator with information concerning the current status of the 
investigational drug as it relates to the Investigator’s obligation for the retention of study 
records. The Investigators should contact the Sponsor prior to disposing of any such records. 
The Sponsor will arrange for continued storage of all records, if necessary and as documented 
in the Clinical Study Agreement. 
The Sponsor will maintain correspondence with the Investigator after study closeout to ensure 
that study documentation is retained for the appropriate amount of time. The Investigator must 
inform the Sponsor immediately if any documents are to be destroyed, to be transferred to a 
different facility, or to be transferred to a different owner. 
In the event the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed-upon designee (e.g., another Investigator). Notice of 
such transfer will be given in writing to the Sponsor. 
19.1.4 ACCESS TO SOURCE DOCUMENTS 
In order to ensure the accuracy of the data collected in the CRFs, representatives from the 
Sponsor, Regulatory Authorities and the Monitor may require access to source documents (i.e. 
patient records, patient charts, laboratory reports, X-ray reports and scans). Anonymity of the 
patient will be maintained at all times. 
19.2 PUBLICATION POLICY 
To avoid disclosures that could jeopardize proprietary rights, Investigators are required to 
submit all publications to the Sponsor prior to submission. The Sponsor will review any such 
submissions within 30 days of receipt.  Therefore, the study site will have the opportunity to 
publish the results of the study, provided that Noxopharm has had the opportunity to review 
and comment on the study site’s proposed publication prior to its being submitted for 
publication with the prior advice of Noxopharm’s Legal Department (intellectual property 
council) and with proper regard to the protection of patients’ identities to a publisher.  
The Sponsor must register the trial prior to commencement and communicate a summary of 
results on an approved registry (e.g. www.clinicaltrials.gov). Publication in medical or scientific 
journals should conform to guidelines set out in the International Committee of Medical Journal 
Editors (ICMJE)1 and consult reporting standards such as the CONSORT2 group and the individual 
journals.  Available on http://www.icmje.org Available on http://www.consort-statement.org  


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20 ADDITIONAL SUBJECT CARE DURING POST-STUDY 
20.1 EMERGENCY CONTACT 
20.1.1 INVESTIGATOR 
The Investigator, or nominated deputy, will be available for consultation by the patient at any 
time during the study period. Names and telephone numbers of staff responsible for the study 
will be made available to the patient. The Investigator must ensure that adequate medical care 
is provided for any adverse events. The Investigator should inform the patient when medical 
care is required for an intercurrent illness. 
20.1.2 SPONSOR 
In an emergency the Investigator should contact both the study sponsor and the Monitor by 
telephone. 
20.2 LIABILITY AND INSURANCE 
The Sponsor provides insurance for study patients to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
With effect from the commencement of the study the sponsor will indemnify study participants. 
 
 


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21 REFERENCES 
1. Siegel RL, Miller KD and Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7–30. 
 
2. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue 
sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. 
J Clin Oncol 2001; 19: 1238–1247. 
 
3. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue  
sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft 
tissue and bone sarcoma group trial. J Clin Oncol 2005; 23: 576–584.  
 
4. Nielsen OS, Judson I, van Hoesel Q, et al. Effect of high-dose ifosfamide in advanced soft 
tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma 
Group. Eur J Cancer 2000; 36: 61–67. 
 
5. Palumbo R, Palmeri S, Antimi M, et al. Phase II study of continuous-infusion high-dose 
ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol 
1997; 8: 1159–1162. 
 
6. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and 
docetaxel compared with gemcitabine alone in patients with metastatic soft tissue 
sarcomas: results of sarcoma alliance for research through collaboration study 002 
[corrected]. J Clin Oncol 2007; 25: 2755–2763. 
 
7. Hensley ML, Blessing JA, Degeest K, et al. Fixed-dose rate gemcitabine plus docetaxel as 
second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group 
phase II study. Gynecol Oncol 2008; 109: 323–328. 
 
8. Harris SJ, Maruzzo M, Thway K, et al. Metastatic soft tissue sarcoma, an analysis of  
systemic therapy and impact on survival. 2015 ASCO Annual Meeting, 2015. 
 
9. Leahy M, Garcia Del Muro X, Reichardt P, et al. Chemotherapy treatment patterns and 
clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment 
and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol 2012; 23: 
2763–2770. 
 
10. Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: a phase III, placebo-controlled 
study of doxorubicin with or without palifosfamide in patients with metastatic soft  
tissue sarcoma. J Clin Oncol 2016; 34: 3898–3905. 
 
11. O’Bryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of adriamycin in human 
neoplasia. Cancer 1977; 39: 1940–1948. 
 
12. Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin 
regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5: 840–850. 
 


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13. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin 
plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a 
randomised controlled phase III trial. Lancet Oncol 2014; 15: 415–423. 
 
14. Le Cesne A, Judson I, Crowther D, et al. Randomized phase III study comparing conventional-
dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus 
recombinant human granulocyte macrophage colony-stimulating factor in advanced soft 
tissue sarcomas: a trial of the European Organization for Research and Treatment of 
Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol 2000; 18: 2676–2684. 
 
15. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus 
ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft 
tissue sarcomas. J Clin Oncol 1993; 11: 1269–1275. 
 
16. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus 
ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of 
the European Organization for Research and Treatment of Cancer Soft Tissue and Bone 
Sarcoma Group. J Clin Oncol 1995; 13: 1537–1545. 
 
17. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone 
for treatment of soft tissue sarcoma: an open-label phase Ib and randomised phase II trial. 
Lancet 2016; 388: 488–497. 
 
18. Alvero, AB, O'Malley D, Brown D, Kelly G, Garg M, Chen W, Rutherford T, Mor G. Molecular 
Mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer. 2006; 106: 
599-608. 
 
19. Kluger, HM, McCarthy MM, Alvero AB, Sznol M, Ariyan S, Camp RL, Rimm DL, Mor G. The X-
linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP 
cleavage by phenoxodiol is associated with carboplatin sensitization. J Transl Med. 2007; 5: 
6-21. 
 
20.  Alvero, AB, Brown D, Montagna M, Matthews M, Mor G. Phenoxodiol-topotecan co-
administration exhibit significant antitumor activity without major adverse side effects. 
Cancer Biol Ther. 2007; 6: 612-617. 
21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumors: revised RECIST guideline (version 
1.1). Eur J Cancer 2009; 45:228-47.  


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22 APPENDICES 
22.1 CONSENT 
A consent form and other related documentation will be provided to participants and authorized 
surrogates 
22.2 SPECIMEN COLLECTION 
22.2.1 CLINICAL LABORATORY TESTS 
Urine pregnancy tests will be read at the site and will be obtained commercially.  All clinical 
laboratory tests (serum chemistry, hematology and urinalysis, and cardiac biomarkers, BNP and 
troponin I) are to be done locally.   
22.2.2 PHARMACOKINETIC, PHARMACODYNAMIC SAMPLES AND ELECTROCARDIOGRAPHIC 
TIMEPOINTS 
22.2.2.1 Collection for Plasma Pharmacokinetic Samples  
Blood samples for idronoxil and doxorubicin will be taken by venipuncture or cannula at time 
points detailed in Sections 11.4.3 and 22.2.2.2. Pre dose samples should be collected within 
15 minutes prior to dosing. The sampling times for collection of blood for analysis of idronoxil, 
its metabolites, doxorubicin and doxorubicinol are listed in Table 7. 
Table 7 
Pharmacokinetic Sampling Times for NOX66 and Doxorubicin  
Monotherapy and Cycle 1 
Cycle               Day 
D 1 
D 2 
D 7 
Day 8 
C1D2 
C1D7  
C1D8 
Hours Post Dose 
Monotherapy e 
NOX 
Dox 
NOX 
NOX 
Pre-Dose 
X 
X 
X 
 
Xd 
 
Xg 
 
0.5 
 
 
 
 
 
Xf 
 
 
1  
X 
 
X 
 
Xe 
 
 
 
2  
X 
 
X 
 
Xe 
 
 
 
3  
X 
 
X 
 
 
 
 
 
4
X
X
Xi 
Xf
6
X
X
Xi 
Xf
8
X
X
Xb
Xb,e
12
Xc
Xc,e
See footnotes on table below. 
 
 
 
 
 


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Cycles 2 to 6 
Cycle 
C2 
C3 
C4 
C5 
C6 
Day 
D2 
D2 
D7 
D8 
D2 
D2 
D7 
D8 
D2 
Hours Post 
Dose 
 NOX 
 
Dox 
NOX 
 
Dox 
NOX NOX NOX 
 
 Dox 
 NOX 
 
Dox 
NOX 
NOX 
NOX 
 
Dox 
Pre-Dose 
Xh 
 
 
 
Xg 
 
Xh 
 
 
 
Xg 
 
Xh 
 
0.5 
  
Xf 
 
 
 
 
  
Xfi 
 
 
 
 
  
Xf 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
X 
Xf 
X 
 
 
 
X 
Xf 
X 
 
 
 
X 
Xf 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
Xb,e 
 
 
 
 
 
Xb,e 
 
 
12 
 
 
 
 
 
Xc,e 
 
 
 
 
 
Xc,e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Samples for idronoxil are to be collected in Potassium Oxalate/Sodium Fluoride containing tubes. 
b Only for TID - 8 hours after the last dose of NOX66 on Day 7 
c Only for BID - 12 hours after the last dose of NOX66 on Day 7 
d Pre dose of NOX66 
e Only for Dose Escalation Cohorts 
f PK sample for Dox  
g Prior to last morning dose of NOX66 
h Prior to the morning dose of NOX66 administration (8or 12 hours after the last dose of NOX66 on Day 1). 
I Only for Dose Expansion Cohort 
The following PK samples can be obtained at the patient’s home if needed: 1) 24-hour sample 
on Day 1 of Monotherapy period, 2) Day 1 of the Washout Period (8 or 12  hours after the last 
dose, of a TID or BID , dosing regimen, respectively) on Day 7 of Monotherapy period], 3) pre-
dose Day 7 and at 8 or 12  hours after the last dose on Day 7 of a TID or BID , dosing regimen, 
respectively for Cycles 1, 3 and 5. 
Blood samples for idronoxil and metabolites will be collected in 4 mL Vacutainer tubes 
containing Potassium Oxalate/Sodium Fluoride as anticoagulant for the preparation of plasma. 
Blood samples for doxorubicin and doxorubicinol will also be collected at specified timepoints 
in pre-chilled 4 mL Vacutainer tubes containing K2EDTA as anticoagulant for the preparation of 
plasma. The details on sample processing will be available in the Laboratory Manual. 
22.2.2.2 Shipping Plasma Pharmacokinetic Samples  
For each cohort, plasma samples will be shipped directly to a nominated laboratory for 
bioanalytical sample analysis. Samples will be packed in sufficient dry ice to last 3 days and 


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prior-shipping notice should be sent to the bioanalytical laboratory. Details on sample packing 
and shipment will be provided in the Laboratory Manual. 
22.2.2.3 ECG Times 
The timepoints for ECG recordings prior to and after administration of idronoxil alone an in 
combination with doxorubicin are listed in Table 8  
ECG Timepoints 
Table 8 
ECG Timepoints 
            Timepoint 
Monotherapy 
Day 1 
Monotherapy  
Day 7 
C1 Day 2 
 
C2-C6 Day 2 
 
              Method 
12-lead  
ECG 
12-lead 
ECG 
Holter 
12-lead 
ECG 
Holter 
12-lead  
ECG 
Pre-Dose (-0.75, -0.5 and -0.25 hrs 
prior to NOX66) 
X 
X 
 
X 
 
 
Pre-Dose (-0.25 hrs prior to NOX66) 
 
 
 
 
 
X 
1 hr post NOX66 dose 
X 
X 
 
X 
 
X 
2 hrs post NOX66 dose 
X 
X 
 
X 
 
X 
5 hrs post NOX66 dose 
X 
X 
 
X 
 
X 
8 hrs post NOX66 dose 
X 
X 
X 
X 
X 
X 
12 hrs post NOX66 dose 
 
 
X 
 
X 
 
24 hrs post NOX66 dose 
 
 
X 
 
X 
 
The following windows are acceptable for performing the ECGs: 
• +/-5 minutes for pre-dose ECGs required at -0.75, -0.5 and -0.25 hours prior to NOX66 
administration. 
• +/-10 minutes for post-dose ECGs required at 1 hour and 2 hours after NOX66 
administration. 
• +/-15 minutes for post-dose ECGs required at 5 hrs and 8 hours after NOX66 
administration. 
22.2.3 GENETIC MUTATIONS AND HISTOPATHOLGY 
Blood samples for genetic mutations will be collected prior to the first dose of NOX66 and on 
Day 21, Cycle 6 (or Early Termination) for both parts.   
Archival tissue sample if available (10 unstained histology slides) will be collected at Screening 
or at any time throughout the study (optional).  
22.2.4 CHEMOKINES, CYTOKINES AND ENOX2 
The laboratory that will assay the plasma samples for chemokines, cytokines and ENOX2 must 
use validated methods. The sampling times for collection of blood for pharmacodynamic 
variables are provided listed in Table 9. 


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Table 9 
Pharmacodynamic Sampling time Points 
Assay 
Blood 
Volume 
(mL) 
Screeninga  
Day 7 Monotherapy 
C3D1 
C6D21/ETb 
 
Dose Escalation 
Chemokines and cytokines 
1 X 4 
X 
X 
X 
X 
Immuno assays and 
lipidomic assays 
4 X 4 
X 
X 
X 
X 
Genetic mutation 
2 x 4 
X 
NA 
NA 
X 
 
Dose Expansion 
Chemokines and cytokines 
1 X 4 
X 
NA 
X 
X 
Immuno assays and 
lipidomic assays 
4 X 4 
x 
 
X 
X 
Genetic mutation 
2 x 4 
X 
 
NA 
X 
aPharmacodynamic samples should be collected only after eligibility confirmation at Screening, or otherwise can be collected 
at Monotherapy Day 1/Cycle 1 Day 1 prior to the first NOX66 administration. 
b PD samples to be collected at Early Termination if the subject discontinues treatment prior to Cycle 6.  
NA= not applicable; ET = Early Termination 
 
The details on pharmacodynamic sample processing and shipping requirements will be 
provided in the Laboratory Manual.  
 


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22.3 INHIBITORS AND INDUCERS OF CYTOCHROME P450 ENZYMES 
A list of medications that can inhibit or induce cytochrome P450 enzymes are shown in  
Table 10 
Inhibitors and Inducers of Cytochrome P450 Enzymes 
 
 
 
 


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INHIBITORS 
Inhibitors compete with other drugs for a particular enzyme thus affecting the optimal level of metabolism of the substrate drug 
which in many cases affect the individual's response to that particular medication, e.g. making it ineffective. 
 A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance. 
 A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance. 
 A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance. 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
 fluvoxamine 
 ciprofloxacin 
 cimetidine 
amiodarone 
efavirenz 
fluoroquinolones 
fluvoxamine 
furafylline1 
interferon 
methoxsalen 
mibefradil 
ticlopidine 
clopidogrel 
thiotepa 
ticlopidine2 
voriconazole
 gemfibrozil2 
 trimethoprim
glitazones 
montelukast1 
quercetin1 
 fluconazole2 
 amiodarone 
efavirenz 
fenofibrate 
fluconazole 
fluvastatin 
fluvoxamine2 
isoniazid 
lovastatin 
metronidazole 
paroxetine 
phenylbutazone 
probenicid 
sertraline 
sulfamethoxazole
sulfaphenazole1 
teniposide 
voriconazole 
zafirlukast 
PPIs: 
esomeprazole 
lansoprazole 
omeprazole 
pantoprazole 
 
Other: 
chloramphenicol
cimetidine 
felbamate 
fluoxetine 
fluvoxamine 
indomethacin 
isoniazid 
ketoconazole 
modafinil 
oral 
contraceptives 
oxcarbazepine 
probenicid 
ticlopidine 
 bupropion 
 cinacalcet 
 fluoxetine 
 paroxetine 
 quinidine1 
 duloxetine 
 sertraline 
 terbinafine 
 amiodarone 
 cimetidine 
celecoxib 
chlorpheniramine 
chlorpromazine 
citalopram 
clemastine 
clomipramine 
cocaine 
diphenhydramine 
doxepin 
doxorubicin 
escitalopram 
diethyl-
dithiocarbamate2 
disulfiram 
HIV 
Antivirals:
 indinavir 
 nelfinavir 
 ritonavir 
 clarithromycin 
 itraconazole1 
 ketoconazole 
 nefazodone 
 saquinavir 
 telithromycin 
 aprepitant 
 erythromycin 
 fluconazole 
 grapefruit 
juice 
 verapamil2 
 diltiazem 
 cimetidine 
amiodarone 
NOT 
azithromycin 


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topiramate 
voriconazole 
halofantrine 
haloperidol 
histamine 
H1 
receptor 
antagonists 
hydroxyzine 
levomepromazine 
methadone 
metoclopramide 
mibefradil 
midodrine 
moclobemide 
perphenazine 
promethazine 
ranitidine 
reduced-
haloperidol 
ritonavir 
ticlopidine 
tripelennamine 
chloramphenicol
boceprevir 
ciprofloxacin 
delaviridine 
diethyl-
dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
starfruit 
telaprevir 
voriconazole 


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INDUCERS 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A4,5,7 
broccoli 
brussel sprouts 
carbamazepine 
char-grilled meat 
insulin 
methylcholanthrene1 
modafinil 
nafcillin 
beta-naphthoflavone1 
omeprazole1 
rifampin 
tobacco 
artemisinin 
carbamazepine 
efavirenz 
nevirapine 
phenobarbital 
phenytoin 
rifampin 
rifampin1 
carbamazepine 
enzalutamide 
nevirapine 
phenobarbital 
rifampin 
secobarbital 
St. John's Wort 
carbamazepine 
efavirenz 
enzalutamide 
norethindrone 
NOT pentobarbital 
prednisone 
rifampicin1 
ritonavir 
St. John's Wort 
dexamethasone 
rifampin 
ethanol 
isoniazid 
HIV Antivirals: 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
enzalutamide 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital2 
phenytoin2 
pioglitazone 
rifabutin 
rifampin1 
St. John's Wort 
troglitazone1