Conditions: Ovarian Neoplasms Fallopian Tube Neoplasms Peritoneal Neoplasms
Keywords: Cantrixil Intraperitoneal
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The main purpose of this study is to determine the safety and feasibility of weekly intra-peritoneal administration of Cantrixil to women with persistent or recurrent ovarian cancer, Fallopian tube cancer or primary peritoneal cancer. The study also aims to determine the maximum tolerated dose of Cantrixil in these patients when administered as a monotherapy or a combination therapy.

Detailed description:
This study is a progressive design with 2 discrete Parts (Part A: Dose escalation, Part B: Dose expansion. Cycle 1/Part A is a dose-finding assessment (dose escalation) to establish the maximum tolerated dose (MTD) of Cantrixil when administered as a single dose once a week for 3 weeks. Cycle2/Part A continues with 3 additional weekly doses of Cantrixil as a monotherapy before an assessment of disease response. In Cycles 3 to 8/Part A, patients will be administered the same once weekly dose of Cantrixil they tolerated in Cycles 1 and 2 (tolerance defined as no dose limiting toxicities \[DLTs\] or unacceptable treatment-related adverse events \[AEs\]) in combination with a limited range of standard chemotherapy agent(s), in order to assess the safety and tolerability of Cantrixil in combination therapy. Standard chemotherapy drugs will be administered at the standard efficacious doses to maintain optimum benefit of known drug combinations for patients.

Once the MTD has been determined in Part A, an additional 12 patients will be recruited in an expansion cohort for Part B. These patients will receive 2 cycles of Cantrixil monotherapy at the MTD, followed by up to 6 cycles of combination therapy.

Patients enrolled into the respective parts of the study may not receive treatments under different parts of the protocol.

To accommodate the intraperitoneal administration of Cantrixil, an in-dwelling, closed catheter or port will be inserted if the patient does not already have one. For intraperitoneal ports, the minimum period between port placement and the first administration of Cantrixil must not be shorter than 7 days.

Patients should begin protocol treatment within a maximum of 28 days of enrolment (i.e., signing of consent form).

Patients will start at Dose Level 0 which is calculated to be the human equivalent of 10% of the severely toxic dose in 10% (STD10) dose in rats (dose that is 1/10 the severely toxic dose in 10% of rats tested). Dose levels -1 and -2 will only be activated if there are 2 DLTs at the Dose Level 0 and -1, respectively. Single patient cohorts will be treated with increasing doses of Cantrixil until an AE is observed that meets the definition of a Dose Limiting Toxicity (DLT) or, in the opinion of the Data Safety Monitoring Committee (DSMC) and the Investigator, is causally related to study treatment and warrants observing additional patients at this dose level; at this point the study will revert to a 3+3 rules based dose escalation study. Once the study enters a 3+3 rules-based design, the study will not revert back to single patient cohorts.

If any unacceptable treatment-related AE or DLT is observed in any cycle, patients may be dose reduced to the next lower dose level of Cantrixil for subsequent doses of therapy. If a second unacceptable treatment-related AE or DLT is observed during any cycle within the same patient, treatment for the patient with Cantrixil will be discontinued. Investigators may continue with the standard chemotherapy at their discretion and if it is considered safe and in the patient's best interest.

If any of the following unacceptable treatment-related AEs or DLTs are observed and unless clearly unrelated to study treatment (e.g., disease progression), treatment at the allocated Cantrixil dose will be discontinued and dose escalation may be considered:

* Hematologic toxicity

  * Grade 4 neutropenia, lasting at least 5 days,
  * Grade 3 or Grade 4 neutropenia associated with fever \>38.5°C,
  * Grade 4 thrombocytopenia lasting at least 5 days,
  * Grade 3 thrombocytopenia associated with severe bleeding in the opinion of the Investigator,
  * Dose delay of ≥3 weeks due to failure to recover counts.
* Any Common Terminology Criteria for Adverse Events (CTCCTCAE) version 4.03 Grade 3 or Grade 4 non haematological toxicity except:

  * Alopecia
  * Grade 3 abdominal pain deemed related to the port or catheter as determined by the treating physician
  * Grade 3 anorexia
  * Grade 3 fatigue
  * Grade 3 nausea and/or vomiting, or diarrhoea, lasting ≤48 hours with or without maximal medical management.
  * Grade 3 dehydration as a result of nausea and vomiting
  * Grade 3 constipation
  * Grade 3 metabolic abnormalities \[hypokalaemia, hypomagnesemia, hypocalcaemia, hypophosphatemia\]) that recovers to Grade 1 or less within 48 hours with or without medical management o• Other serious adverse events (SAEs) which, in the opinion of the treating Investigator, are related to investigational product and necessitate temporary or permanent cessation of administration o• Treatment delays of ≥3 weeks due to any treatment-related non-haematological toxicity will constitute a DLT All patients who discontinued from the study (i.e. are now Off Therapy/ End of Therapy) treatment will progress to follow-up unless the patient withdraws consent.

The initiation of each new cycle of Cantrixil will be at the discretion of the Investigator and will depend on the potential or measurable benefit to the patient assuming continued tolerability and adequate organ function.

Cantrixil treatment will be stopped due to RECIST version 1.1 defined disease progression observed after at least 4 cycles of therapy, recurrence of unacceptable toxicity after 1 Cantrixil dose reduction or patient consent withdrawal. Note that patients with progressive disease at the end of 2 cycles of Cantrixil monotherapy will not be taken off therapy if Cantrixil has been well tolerated. Pre-clinical data would suggest that the maximum benefit from Cantrixil will be realised as a combination therapy, hence all patients will have the opportunity to continue receiving Cantrixil as a combination therapy. Additionally, patients receiving combination therapy that are observed to have progressive disease as identified by RECIST version 1.1 criteria but who, in the opinion of the Investigator, continued to derive clinical benefit may continue Cantrixil treatment. Patients may also be discontinued from study treatment if the Investigator considers continuing therapy is not in the patient's best interest. All patients discontinued from study treatment will progress to follow-up unless the patient withdraws consent.

Tumour assessment via radiological imaging will be conducted during screening and every 6 weeks after the start of therapy, i.e. at the end of monotherapy and then after every 2 cycles of combination therapy. Either contrast-enhanced magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) may be used, but once a modality is used at baseline this must be used consistently for that patient throughout their participation on the study. Other imaging is not mandatory, but may be performed if clinically indicated.

Adverse events will be monitored for the duration of the study from the time of informed consent. Blood samples will be collected weekly for standard safety testing, or more frequently if clinically relevant, during the study. Additional volumes of blood will be collected before and after administration of Cantrixil for pharmacokinetic (PK) analysis (4 mL per time point as per the proposed PK schedule and for any exploratory studies (at baseline, end of Cycle 2 and end of treatment, 15 to 20 mL at each time-point).

Arms:
arm 1: Part A (Dose Escalation):

Part A is a Dose Escalation study to determine the Maximum Tolerated Dose of Cantrixil as a monotherapy.

The tolerance of Cantrixil in combination with standard chemotherapy agents will also be examined.

Part B (Expansion Cohort):

An expansion cohort of an additional 12 patients will be recruited at the MTD.

Interventions: intervention 1: Part A: Dose Escalation of Cantrixil intervention 2: Part B: Expansion Cohort of Cantrixil
Intervention descriptions: intervention 1: Cantrixil will be administered via the intraperitoneal route only. The dose of study drug that each participant will receive will depend on how far the study has progressed when the participant enrols. There are 9 potential doses of Cantrixil, they are 0.06, 0.12, 0.24 (starting dose), 0.6, 1.25, 2.5, 5, 10, or 20 mg/kg. The dose each participant receives will remain the same during the study, unless it needs to be reduced for safety reasons. The dose will not be increased.

Each participant will receive the study drug once a week during the first two cycles; each cycle is 21-days (three weeks); the MTD will be determined during Cycle 1 only. If after two cycles of monotherapy, the patient tolerates Cantrixil adequately, they may continue to receive Cantrixil once a week and will also begin combination chemotherapy for another 6 cycles. Participants will receive no more than 8 cycles of study drug. intervention 2: Once the MTD has been established, an expansion cohort will be recruited at the MTD. An additional 12 patients will be recruited in this cohort on top of those recruited in Part A at the MTD. These patients will be subjected to the same intervention described in Part A with 2 cycles of monotherapy followed by up to 6 cycles of combination therapy.

Protocol document:
Prot_000.pdf: 
Phase I Study of Intraperitoneal Cantrixil in Patients with Persistent or Recurrent 
Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT02903771
Study Protocol
Date 
30 April 2018


Clinical Study Protocol 
 
 
 
 
 
 
 
 
Phase I Study of Intra-peritoneal Cantrixil in Patients with 
Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer 
or Primary Peritoneal Cancer. 
 
Protocol Number: 
NVGN-002-101 
IND Number: 
123275 
Product: 
Cantrixil (TRX-E-002-1 in 20% Dexolve-7) 
 
Indication: 
Ovarian, Fallopian Tube, or Peritoneal Cancer 
 
Clinical Phase: 
Phase I 
Principal 
Investigators: 
 
Principal Investigator  
Dr Don Dizon (Lead PI in USA) 
A/Prof Jim Coward (Lead PI in Australia) 
Sponsor: 
 
Kazia Therapeutics Limited 
Three International Towers 
Level 24, 300 Barangaroo Avenue 
Sydney NSW 2000, Australia 
Australia 
Version: 
 
4.0 
Date: 
 
30 April 2018 
This protocol is the confidential property of Kazia Therapeutics Limited, and is 
intended solely for the guidance of this clinical investigation. This protocol may 
not be disclosed to parties not associated with the clinical investigation or used 
for any other purpose without the prior written consent of Kazia Therapeutics 
Limited. 


CONFIDENTIAL 
 
Sponsor:  Kazia Therapeutics Limited 
Version:  4.0 
Date:  30 April 2018 
Clinical Study Protocol 
Protocol Number:  NVGN-002-101 
IND Number:  123275 
 
 
Page 2 of 92 
DOCUMENT HISTORY 
 
Version 
Date 
Reason for amendment 
Summary of changes 
Substantial 
amendment 
(Y/N) 
2.0 
07 
September 
2016 
Incorporate changes as 
per FDA recommendations 
Define allowed 
combination 
chemotherapies and 
dosing schedules. 
Update eligibility criteria 
as per FDA advice. 
Include assessment by 
the DSMC/B of Cantrixil 
monotherapy PK data 
before beginning 
combination therapy for 
each patient.  
Amend errors or 
ambiguities in language 
for improved clarity. 
Y 


CONFIDENTIAL 
 
Sponsor:  Kazia Therapeutics Limited 
Version:  4.0 
Date:  30 April 2018 
Clinical Study Protocol 
Protocol Number:  NVGN-002-101 
IND Number:  123275 
 
 
Page 3 of 92 
 
3.0 
26 June 
2017 
Add a mechanism to allow 
extended access beyond 
the first 8 cycles; Remove 
Part C; Incorporate 
Changes as per HREC 
recommendations 
Add an additional 
extended access cohort 
to the study. 
Remove all references to 
Part C. 
Update names and 
contact details of Principal 
Investigators and Sites. 
Update language to 
improve clarity of protocol 
and correct errors that 
had been identified. 
 
Y 
4.0 
30 April 
2018 
Update Novogen name 
change approved at AGM 
held on 15th November 
2017;  
Update Corporate Address 
post move 5th February 
2018; 
 
 
 
 
Remove Biomarker sample 
from part B 
 
 
Update Quintiles name 
change announced 
November 2017 
 
 
Change all references of 
Novogen to Kazia 
Therapeutics to reflect the 
approved name. 
Update the Corporate 
address to Three 
International Towers 
Level 24, 300 Barangaroo 
Avenue 
Sydney NSW 2000, 
Australia; 
Remove all references to 
the collection of the 
Biomarker sample in Part 
B. 
 
Changed all references of 
Quintiles to IQVIA 
Y 
 
 


 
CONFIDENTIAL 
 
Sponsor:  Kazia Therapeutics Limited 
Version:  4.0 
Date:  30 April 2018 
Clinical Study Protocol 
Protocol Number:  NVGN-002-101 
IND Number:  123275 
 
 
 
Page 4 of 92 
 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS..................................................................................4 
2 
TABULATED PROTOCOL SUMMARY .......................................................8 
3 
LIST OF ABBREVIATIONS .........................................................................19 
4 
INTRODUCTION ..........................................................................................21 
4.1 
Background Information .................................................................................21 
4.1.1 
Pre-Clinical Findings ................................................................................. 22 
4.2 
Rationale .........................................................................................................24 
4.3 
Risk Assessment .............................................................................................25 
4.4 
Urgent safety measures ...................................................................................25 
5 
STUDY OBJECTIVES...................................................................................26 
5.1 
Primary Objectives .........................................................................................26 
5.2 
Secondary Objectives .....................................................................................26 
5.3 
Exploratory Objectives ...................................................................................26 
6 
INVESTIGATIONAL PLAN .........................................................................27 
6.1 
Overall Study Design ......................................................................................27 
6.1.1 
Data Safety Monitoring Committee/Board ................................................ 35 
6.1.2 
Dose Escalation Criteria ............................................................................ 35 
6.1.3 
Study Stopping Rules................................................................................. 36 
6.1.4 
Discussion of Study Design ....................................................................... 37 
6.2 
Study Population .............................................................................................38 
6.2.1 
Subject Inclusion Criteria .......................................................................... 38 
6.2.2 
Subject Exclusion Criteria ......................................................................... 40 
6.2.3 
Restrictions ................................................................................................ 41 
6.2.3.1 
Avoidance of Pregnancy .................................................................................42 
6.2.3.2 
Acceptable Forms of Contraception ...............................................................42 
6.2.3.3 
Time Period for the Collection of Pregnancy Information .............................43 
6.2.3.4 
Follow-up in the Event of a Pregnancy ..........................................................43 
6.2.4 
Subject Withdrawals .................................................................................. 43 
7 
STUDY TREATMENT ..................................................................................45 
7.1 
Investigational Product(s) ...............................................................................45 
7.1.1 
Supply, Packaging and Labelling .............................................................. 45 
7.1.2 
Storage and Handling Procedures .............................................................. 45 
7.1.3 
Accountability ............................................................................................ 45 
7.2 
Dosage and Administration ............................................................................46 
7.3 
Treatment Strategy ..........................................................................................47 
7.4 
Warnings and Precautions ..............................................................................48 
7.5 
Prior and Concomitant Medication .................................................................48 
7.6 
Method of Assigning Subjects to Treatment Groups......................................48 
7.7 
Randomisation Procedures (Not applicable) ..................................................49 


 
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Date 30 April 2018 
Clinical Study Protocol  
Protocol Number:NVGN-002-101 
IND Number:123275 
 
 
 
 
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7.8 
Maintenance of Randomisation Codes (Not applicable) ................................49 
7.9 
Blinding (Not applicable) ...............................................................................49 
8 
STUDY PROCEDURES ................................................................................50 
8.1 
Pharmacokinetic Assessments ........................................................................50 
8.2 
Efficacy Assessments .....................................................................................50 
8.3 
Safety Assessments .........................................................................................52 
8.3.1 
Adverse Events .......................................................................................... 52 
8.3.2 
Reporting of Adverse Events ..................................................................... 53 
8.3.3 
Categorisation of Adverse Events.............................................................. 53 
8.3.4 
Causal Relationship Assessment ............................................................... 54 
8.3.5 
Action Taken.............................................................................................. 54 
8.3.6 
Outcome ..................................................................................................... 54 
8.3.7 
Coding of Adverse Events ......................................................................... 55 
8.3.8 
Pregnancy Reporting.................................................................................. 55 
8.4 
Clinical Laboratory Safety Tests ....................................................................55 
8.5 
Clinical Safety Assessments ...........................................................................56 
8.5.1 
Physical Examination ................................................................................ 56 
8.5.2 
Vital Signs.................................................................................................. 56 
8.5.3 
12-Lead Electrocardiogram (ECG) ............................................................ 56 
8.5.4 
Medical History ......................................................................................... 56 
8.6 
Follow-up Assessments ..................................................................................57 
9 
DATA COLLECTION ...................................................................................58 
10 
EVALUATION OF STUDY DATA ..............................................................60 
10.1 
Evaluation of Pharmacokinetic Parameters ....................................................60 
10.2 
Evaluation of Pharmacodynamic/Efficacy Measures .....................................60 
10.3 
Evaluation of Safety........................................................................................60 
11 
STATISTICAL METHODS ...........................................................................61 
11.1 
Sample Size Determination ............................................................................61 
11.2 
Subject Populations for Analyses ...................................................................62 
11.3 
Pharmacokinetic Analysis...............................................................................62 
11.4 
Efficacy Analysis ............................................................................................63 
11.5 
Exploratory Analysis ......................................................................................63 
11.6 
Safety Data Analysis .......................................................................................63 
12 
STUDY REPORT ...........................................................................................66 
13 
REGULATORY AND ETHICAL ISSUES ...................................................67 
13.1 
Regulatory and Ethics Review and Approval .................................................67 
13.2 
Informed Consent ...........................................................................................67 
13.3 
Indemnity and Compensation .........................................................................68 
14 
STUDY MANAGEMENT .............................................................................69 
14.1 
Quality Assurance and Quality Control ..........................................................69 
14.2 
Protocol Adherence.........................................................................................69 


 
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Date 30 April 2018 
Clinical Study Protocol  
Protocol Number:NVGN-002-101 
IND Number:123275 
 
 
 
 
Page 6 of 92 
14.3 
Documents Necessary for Initiation of Study .................................................69 
14.4 
Study Monitoring ............................................................................................70 
14.5 
Study Closure ..................................................................................................70 
14.6 
Study Record Retention ..................................................................................71 
14.7 
Publication Policy ...........................................................................................71 
15 
REFERENCES ...............................................................................................72 
16 
STUDY SCHEDULE .....................................................................................75 
17 
PROTOCOL SIGNATURES .........................................................................80 
 
 
 


 
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Sponsor:  Kazia Therapeutics Limited 
Version 4.0 
Date 30 April 2018 
Clinical Study Protocol  
Protocol Number:NVGN-002-101 
IND Number:123275 
 
 
 
 
Page 7 of 92 
LIST OF TABLES 
Table 1 
Permitted Combination Therapies ................................................................... 27 
Table 2 
Doses at each Dose Level ................................................................................ 28 
Table 3 
3+3 Design Dose-escalation Plan .................................................................... 36 
Table 4 
Schedule of Assessments ................................................................................. 76 
Table 5 
Proposed PK Schedule (Part A and Part B) ..................................................... 78 
Table 6 
Schedule of Assessments in Follow-up ........................................................... 79 
Table 7 
Evaluation of Best Overall Response in Patients without Initial Measurable 
Disease and who are Evaluable as proposed by GCIG ...................................................... 91 
Table 8 
Best Overall Response in Patients with Measurable Disease and who are 
Evaluable by CA-125 as proposed by GCIG ..................................................................... 91 
Table 9 
Definition of Progression as proposed by GCIG ............................................. 92 
 
 
 
LIST OF FIGURES 
Figure 1 
Proposed Dosing Schema ................................................................................ 34 
 
 
 
APPENDICES 
Appendix A: Study Contacts..............................................................................................82 
Appendix B: Procedures for the placement of the Intraperitoneal port/ catheter and 
administration of Intraperitoneal therapy ...........................................................................84 
Appendix C: Evaluation of response and progression using gynecological cancer 
intergroup (GCIG) response criteria ..................................................................................89 
 
 
 


 
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Date 30 April 2018 
Clinical Study Protocol  
Protocol Number:NVGN-002-101 
IND Number:123275 
 
 
 
 
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2 TABULATED PROTOCOL SUMMARY 
 
Name of Sponsor/Company: 
Kazia Therapeutics Limited 
Name of Finished Product(s): 
Cantrixil  
Name of Active Ingredient(s): 
TRX-E-002-1 (in 20% Dexolve-7) 
Title of Study:  
Phase I Study of Intra-peritoneal Cantrixil in Patients with Persistent or Recurrent Ovarian Cancer, 
Fallopian Tube Cancer or Primary Peritoneal Cancer 
Principal Investigators: 
 Dr Don Dizon (National PI), Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA 
A/Prof Kathleen Moore, Oklahoma Health Sciences Center, Oklahoma City, OK, USA 
Dr Minal Barve, Mary Crowley Cancer Center, Dallas, TX, USA 
A/Prof Jermaine (Jim) Coward (National PI), ICON Cancer Care, South Brisbane, QLD, Australia  
Dr Ganessan Kichenadasse, Flinders Medical Centre, Adelaide, SA, Australia 
Prof Paul Harnett, Westmead Adults Hospital, Westmead, NSW, Australia 
Investigational Site: 
The study will be conducted in approximately 5 to 6 study centres in Australia and the United States 
(US). 
Clinical Phase: 
Phase I 
Objectives: 
Primary Objective 
• 
To determine the maximum tolerated dose (MTD) of Cantrixil when delivered as a single agent, 
administered intraperitoneally, at a weekly administration frequency.  
• 
To evaluate the safety and tolerability of Cantrixil delivered via intraperitoneal administration 
as a single agent and in combination with standard chemotherapy when administered weekly. 
• 
To characterise the pharmacokinetics (PK) of intraperitoneal Cantrixil when delivered as a 
single agent and in combination with standard chemotherapy. 
Secondary Objectives 
• 
To evaluate progression free survival (PFS). 
• 
To evaluate the time to paracentesis and the volume of malignant ascites drained at each 
paracentesis event (for those patients with malignant ascites). 
• 
To evaluate the potential anti-cancer activity of Cantrixil using Response Evaluation Criteria in 
Solid Tumours (RECIST) criteria, version 1.1 and CA-125 measurements. 
• 
To evaluate the change in cancer antigen 125 (CA-125) in peripheral blood before and after 
treatment with Cantrixil. 
Exploratory Objectives 
• 
To evaluate the safety, tolerability and activity of Cantrixil when administered intraperitoneally 
as a single agent and in combination at a twice-weekly administration frequency. 


 
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Clinical Study Protocol  
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IND Number:123275 
 
 
 
 
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• 
To evaluate the change in the number of circulating epithelial tumour cells (CETCs) in 
peripheral blood and malignant ascites (if present) before and after treatment with Cantrixil. 
• 
To evaluate the clonogenicity of CETCs in peripheral blood and malignant ascites (if present) 
before and after treatment with Cantrixil. 
• 
To evaluate the expression of stem cell markers, CD44 and ALDH in colonies isolated in the 
clonogenicity assays. 
Methodology: 
This study is a progressive design with 2 discrete Parts (Part A: Dose escalation, Part B: Dose 
expansion). Cycle 1/Part A is a dose-finding assessment (dose escalation) to establish the MTD of 
Cantrixil when administered as a single dose once a week for 3 weeks. Cycle 2/Part A continues with 3 
additional weekly doses of Cantrixil as a monotherapy before an assessment of disease response. In 
Cycles 3 to 8/Part A, patients will be administered the same once-weekly dose of Cantrixil they tolerated 
in Cycles 1 and 2 (tolerance defined as no dose limiting toxicities [DLTs] or unacceptable adverse events 
[AEs]) in combination with standard chemotherapy agent(s), in order to assess the safety and tolerability 
of Cantrixil in combination therapy. Standard chemotherapy drugs will be administered at the standard 
efficacious dose and dosing schedule to maintain optimum benefit of known therapeutic agents for 
patients. Treating physicians may choose the combination therapy from the list in Table 1 taking into 
consideration factors such as pre-existing comorbidities, prior toxicities and responses as well as patient 
and physician preferences.  
Combination chemotherapy may not be administered until 24 hours after administration of Cantrixil to 
avoid any adverse drug-drug interactions. All combination therapies and concomitant medications must 
be diligently recorded in the patients’ electronic case report form (eCRF).  
Once the MTD has been determined in Part A/Cycle 1, an additional 12 patients will be recruited in an 
expansion cohort for Part B. These patients will receive 2 cycles of Cantrixil monotherapy at the MTD, 
followed by up to 6 cycles of combination therapy, selected by the treating physician from Table 1.  
Patients enrolled into the respective parts of the study may not receive treatments under different parts of 
the protocol e.g., if a patient enters Part A, she may not also continue to Part B even if she is considered 
to have completed Part A. 
To accommodate the intraperitoneal administration of Cantrixil, an in-dwelling, closed catheter or port 
will be inserted if the patient does not already have one. For intraperitoneal ports, the minimum period 
between port placement and the first administration of Cantrixil must not be shorter than 7 days. For 
other intraperitoneal access devices, the period may be shorter if adequate stability and/or healing of the 
delivery system’s insertion site is confirmed by the treating physician. 
Patients should begin protocol treatment within a maximum of 28 days of enrolment (i.e., signing of 
consent form). 
Patients will start at Dose Level 0 (see Table 2) which is calculated to be the human equivalent of 10% 
of the STD10 dose in rats (dose is 1/10 the severely toxic dose in 10% of rats tested). Dose levels -1 
and -2 will only be activated if there are 2 DLTs at the Dose Level 0 and -1, respectively. Single patient 
cohorts will be treated with increasing doses of Cantrixil until an AE is observed during Part A/Cycle 1 
that meets the definition of a DLT or, in the opinion of the Data Safety Monitoring Committee/Board 
(DSMC/B) and the Investigator, warrants observing additional patients at this dose level; at this point the 
study will revert to a 3+3 rules-based dose escalation study. The decision to expand from single patient 
cohorts to 3 patient cohorts is critical for the safety of participants and will be made with input from the 
Investigator and DSMC/B responsible for this study. Once the study enters a 3+3 rules-based design, the 


 
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Clinical Study Protocol  
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IND Number:123275 
 
 
 
 
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study will not revert back to single patient cohorts.  
If any unacceptable AE or DLT is observed in any cycle, patients may be dose reduced to the next lower 
dose level of Cantrixil for subsequent doses of therapy. If a second unacceptable AE or DLT is observed 
during any cycle within the same patient, treatment for the patient with Cantrixil will be discontinued. 
Investigators may continue with the standard chemotherapy at their discretion and if it is considered safe 
and in the patient’s best interest.  
If any of the following unacceptable AEs or DLTs are observed and unless clearly unrelated to study 
treatment (e.g., disease progression), treatment at the currently allocated Cantrixil dose will be paused. 
At this point a dose reduction may be considered or the treatment may be terminated, depending on what 
is considered by the investigator to be in the participant’s best interest.: 
• 
Hematologic toxicity 
o 
Grade 4 neutropenia, lasting at least 5 days, 
o 
Grade 3 or Grade 4 neutropenia associated with fever >38.5°C,  
o 
Grade 4 thrombocytopenia lasting at least 5 days,  
o 
Grade 3 thrombocytopenia associated with severe bleeding in the opinion of the 
Investigator, 
o 
Dose delay of ≥3 weeks due to failure to recover counts. 
• 
Any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or 
Grade 4 non-haematological toxicity except: 
o 
Alopecia 
o 
Grade 3 abdominal pain deemed related to the port or catheter as determined by the 
treating physician 
o 
Grade 3 anorexia 
o 
Grade 3 fatigue 
o 
Grade 3 nausea and/or vomiting, or diarrhoea, lasting ≤48 hours with or without 
maximal medical management. 
o 
Grade 3 dehydration as a result of nausea and vomiting 
o 
Grade 3 constipation 
o 
Grade 3 metabolic abnormalities [hypokalaemia, hypomagnesemia, hypocalcaemia, 
hypophosphatemia]) that recovers to Grade 1 or less within 48 hours with or without 
medical management 
• 
Other serious adverse events (SAEs) which, in the opinion of the treating Investigator, 
necessitate temporary or permanent cessation of administration 
• 
Treatment delays of ≥3 weeks due to any non-haematological toxicity will constitute a DLT 
All patients who discontinue (i.e. are now Off Therapy/ End of Therapy) from the study treatment will 
progress to follow-up unless the patient withdraws consent.  
The initiation of each new cycle of Cantrixil will be at the discretion of the Investigator and will depend 
on the potential or measurable benefit to the patient assuming continued tolerability and adequate organ 
function. 
Cantrixil treatment will be stopped due to RECIST version 1.1 defined disease progression observed 
after at least 2 cycles of combination therapy, recurrence of unacceptable toxicity after 1 Cantrixil dose 
reduction or patient consent withdrawal. Note that patients with progressive disease at the end of 


 
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Clinical Study Protocol  
Protocol Number:NVGN-002-101 
IND Number:123275 
 
 
 
 
Page 11 of 92 
2 cycles of Cantrixil monotherapy will not be taken off therapy if Cantrixil has been well tolerated. 
Pre-clinical data would suggest that the maximum benefit from Cantrixil will be realised as a 
combination therapy, hence all patients will have the opportunity to continue receiving Cantrixil as a 
combination therapy. Additionally, patients receiving combination therapy that are observed to have 
progressive disease as identified by RECIST version 1.1 criteria but who, in the opinion of the 
Investigator, continued to derive clinical benefit may continue Cantrixil treatment. Patients may also be 
discontinued from study treatment if the Investigator considers continuing therapy is not in the patient’s 
best interest. All patients discontinued from study treatment (i.e. are now Off Therapy/ End of Therapy) 
will progress to follow-up unless the patient withdraws consent.  
Tumour assessment via radiological imaging will be conducted during screening and every 6 weeks after 
the start of therapy, i.e. at the end of monotherapy and then after every 2 cycles of combination therapy. 
The screening period is up to 28 days before the Cycle 1 Day 1 dose of Cantrixil. Either contrast-
enhanced magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) may be 
used, but once a modality is used at baseline this must be used consistently for that patient throughout 
their participation on the study. Other imaging is not mandatory, but may be performed if clinically 
indicated.  
Adverse events will be monitored for the duration of the study from the time of informed consent. Blood 
samples will be collected weekly for standard safety testing, or more frequently if clinically relevant, 
during the study. Additional volumes of blood will be collected before and after administration of 
Cantrixil for PK analysis (4 mL per time point as per the proposed PK schedule [Table 5]) and for any 
exploratory studies (at baseline, end of Cycle 2 and End of Therapy, 15 to 20 mL at each time-point). 
Part A (Dose escalation of Cantrixil as a monotherapy):  
Cycle 1  
Following placement of a port or catheter, eligible patients will be administered a single dose of the 
study treatment Cantrixil (TRX-E-002-1 formulated in Dexolve-7) intraperitoneally once a week for 
3 weeks. Patients will be monitored for DLTs over the 21-day cycle (Cycle 1).  
Blood samples will be collected weekly at each scheduled visit for standard safety testing, or more 
frequently if clinically relevant. Results of the safety assessments must be available prior to Cantrixil 
administration to ensure that all assessments still meet inclusion criteria as described in Section 6.2.1 and 
it is safe to proceed to the next dose of treatment. Treatment delays of up to three weeks are allowed for 
recovery without being classified as a protocol deviation or a dose limiting toxicity. 
Patients will continue to be monitored until they meet the study discontinuation criteria but will only be 
evaluable for DLTs that define the MTD of Cantrixil as a monotherapy during Cycle 1/Part A.  
Patients will start at Dose Level 0 (see Table 2) which is calculated to be the human equivalent of 10% 
of the STD10 dose in rats (dose is 1/10 the severely toxic dose in 10% of rats tested). Dose levels -1 and 
-2 will only be activated if there are 2 DLTs at the Dose Level 0 and -1, respectively. Single patient 
cohorts will be treated with increasing doses of Cantrixil until an AE is observed during Part A/Cycle 1 
that meets the definition of a DLT or in the opinion of the DSMC/B and the Investigator, warrants 
observing additional patients at this dose level; at this point the study will revert to a 3+3 rules-based 
dose escalation study (see Section 6.1.2). The decision to expand from single patient cohorts to 3 patient 
cohorts is critical for the safety of participants and will be made with input from the Investigator and 
DSMC/B responsible for this study (see Section 6.1.1). 
Cycle 2 
Patients that are still on study treatment at the end of Cycle 1/Part A will receive another cycle of 
Cantrixil monotherapy with once weekly dosing before disease assessment. Note that a disease 


 
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assessment will be conducted at the end of monotherapy but patients will not automatically be removed 
from therapy at this time-point if they have progressive disease as defined by RECIST version 1.1 
criteria. This is because the preclinical data strongly suggests that the benefit of Cantrixil will most likely 
be realised as a combination therapy. All patients will, therefore, have the opportunity to progress to a 
combination therapy with Cantrixil. 
Patients that have not discontinued from the study at the end of Cycle 2 will proceed to Cycles 3 to 
8/Part A of the study.  
Cycles 3 to 8 (Cantrixil in Combination with Standard Chemotherapy) 
Patients that progress to Cycles 3 to 8/Part A will continue on the same dose level of Cantrixil that they 
tolerated in Cycles 1 and 2/Part A, but in combination with systemic chemotherapy selected from Table 
1 by the treating physician/Investigator.  
During Cycles 3 to 8/Part A, patients will be administered Cantrixil once per week for each 21-day 
cycle. In addition to Cantrixil, patients will receive the chemotherapy selected by the Investigator 
according to the schedule in Table 1. Before administration of the combination chemotherapy, the PK 
results for each patient from Part A/ Cycle 1 will be reviewed by the DSMC to ensure that the PK profile 
of Cantrixil is indeed compatible with the proposed schedule for the combination chemotherapy agent. 
With the anticipated PK profile of Cantrixil, combination therapy should not be administered until 
24 hours after any dose of Cantrixil to avoid any adverse drug-drug interactions. All combination 
therapies and concomitant medications must be diligently recorded in the patient’s eCRF. 
Part B (Expansion Cohort at MTD): 
Once the MTD has been established, an expansion cohort will be recruited at the MTD. An additional 
12 patients will be recruited in this cohort on top of those recruited in Part A at the MTD. These patients 
will be subjected to the same intervention described above with 2 cycles of monotherapy followed by up 
to 6 cycles of combination therapy. 
Continued Access for Patients: 
Patients who complete the planned 8 cycles of treatment and in whom the Investigator feels there has 
been clinical benefit, have the option to continue to receive Cantrixil. This will be based on discussion 
between the Sponsor and the Investigator, all of which must be documented.  
It is at the discretion of the Investigator whether this continued treatment is a maintenance monotherapy 
or a combination chemotherapy.  
All patients that are provided continued access to Cantrixil are considered to be ongoing participants in 
this trial and hence, must agree to on-going data collection for monitoring safety, progression and 
survival. 
Number of Subjects: 
Six to 54 (includes up to 42 in Part A and12 in Part B) patients with persistent or recurrent ovarian 
cancer, fallopian tube cancer or primary peritoneal cancer. 
Main Criteria for Inclusion: 
Patients with the following disease criteria are eligible for this study:  
1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary 
peritoneal cancer. The original diagnosis must be verified by a histology report. All histological 
sub-types and all grades of disease are eligible to participate; grade, histological sub-type and 
breast cancer susceptibility gene (BRCA) status must be recorded at study entry. 
2. Patients must be female and at least 18 years old. Patients may be women of child-bearing 
potential as long as they are not pregnant or breast-feeding and able to adopt adequate 


 
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contraception as described in section 6.2.3.1. 
3. Patients with malignant ascites are eligible to participate; paracentesis will be conducted before 
the administration of Cantrixil. Drainage of the maximum volume of ascites should be 
performed according to local standard operating procedures before administration of Cantrixil. 
4. Patients must have completed at least two (2) or more prior regimens (including adjuvant 
therapy) for their ovarian, Fallopian tube or primary peritoneal cancer prior to participation in 
the current study; all prior therapies must be recorded at baseline. Patients that have received 
prior intraperitoneal therapy are eligible for this study. Patients should have failed standard of 
care drugs prior to being eligible to be part of the proposed study. 
 
5. Patients must have platinum-resistant relapsed disease, platinum refractory disease, or have 
documented intolerance to platinum therapy. Patients will not be eligible based on rising 
CA-125 levels alone, patients must have other clinical symptoms (such as malignant 
ascites) or radiological tumour measurements that support disease recurrence or 
progression. 
6. At least 4 weeks must have passed from any previous therapy and any toxicities from prior 
therapies (6 weeks for bevacizumab, nitrosoureas or mitomycin C treatment) must have 
resolved to less than or equal to Common Terminology Criteria for Adverse Events (CTCAE 
version 4.03) Grade 1 with the exception of alopecia, Grade 2 prior platinum-therapy related 
neuropathy and Grade 2 anaemia.  
7. Patients must have a performance status of Eastern Cooperative Oncology Group (ECOG) 
0 to 2 and, in the Investigator’s opinion, be able to complete at least a major part of the study. 
8. Patients must be willing and able to undergo insertion of a port or catheter for intraperitoneal 
access; the type of port or catheter used will be recorded. 
9. Patients may have measurable or non-measurable disease; disease response and progression will 
be measured and assessed according to RECIST version 1.1 criteria using contrast CT, MRI and 
CA-125 measurements. 
10. Patients must have acceptable hepatic and marrow function as defined below: 
11. Absolute neutrophil count >1.5 x 109/L 
12. Platelets >100 x 109/L 
13. Total bilirubin; <2.5 times the institutional upper limit of normal (ULN) 
14. Haemoglobin (Hb) of >10 g/dL; patients with Hb >9g/dL will be considered for this study if 
they have not received a transfusion or other bone marrow support. Patients with Hb >10 g/dL 
that have received a recent transfusion will only be eligible if there has been a wash-out period 
of 7 days for rhesus factor and 10 days for platelet transfusions, respectively. 
15. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ alanine 
aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤2.5 x institutional 
ULN.  
16. Serum creatinine <1.5 x ULN 
17. Prothrombin time (PT) or international normalised ratio (INR) ≤1.5 x ULN and activated partial 
thromboplastin time (aPTT) ≤1.5 x ULN if not on anticoagulation treatments. 
18. Patients must be willing and able to comply with all study requirements, including treatment 
timing and/or nature of required assessments and treatment at designated study centre. 
19. Each participant must be adequately informed about the purpose of the study; potential benefits 


 
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and risks; their right to refuse participation or to withdraw consent at any time; institutional 
affiliation and potential competing interests of the researcher; and sources of study funding and 
have signed and dated a written informed consent form. 
Main Criteria for Exclusion: 
1. Patients who have had chemotherapy, biologic therapy, immunotherapy, or radiotherapy within 
4 weeks (6 weeks for bevacizumab, nitrosoureas or mitomycin C) prior to entering the study. 
2. Patients must not have had major surgery within 4 weeks prior to screening. 
3. Patients may not have received any other investigational medicinal products (IMPs) or 
participated in any other interventional clinical research studies within 4 weeks of the first 
Cantrixil administration. 
4. Patients receiving any medications or substances that are strong inhibitors or inducers of 
cytochrome P450 (CYP)1A2, CYP2B6 and CYP3A4 or those substances with narrow 
therapeutic index are not to be enrolled. These compounds are prohibited from screening until 
completion of end of therapy or first post-treatment follow-up visit. For a list of prohibited 
medications see the University of Indiana Clinical Pharmacology Department’s P450 Drug 
Interaction Table (http://medicine.iupui.edu/clinpharm/ddis/main-table/). Note: the use of 
paclitaxel is allowed, but only 24 hours after Cantrixil administration. 
5. Patients deemed by the Investigator to be at high risk of bowel perforation or obstruction are 
excluded, including but not limited to any one or more of the following;  
• 
Patients with a recent history (previous 12 months) of bowel obstruction prior to study 
entry  
• 
Patients with CT scans that suggest invasion of bowel by tumour 
• 
Patients with symptoms to suggest impending bowel obstruction  
• 
Patients with prior whole abdominal radiotherapy 
• 
Patients with chronic inflammatory bowel diseases such as Crohn’s disease or 
ulcerative colitis  
6. Patients may not have uncontrolled or severe systemic diseases or psychiatric conditions, which 
in the treating physician’s opinion makes it unsafe for the patient to participate in the study or 
would hinder compliance with the protocol. Screening for chronic conditions is not required. 
7. Patients that are pregnant, lactating, or unable to adopt adequate contraception are excluded. 
Women of childbearing potential must have a negative pregnancy test within 7 days prior to 
screening. 
8. Patients with active hepatitis B or C.   
9. Patients known to have tested positive for human immunodeficiency virus (HIV) 
10. Patients with a known hypersensitivity to or serious reaction to benzopyrans are excluded. 
Test Product, Dose and Route 
 of Administration: 
Cantrixil, escalating doses from 0.24 mg/kg to 20 mg/kg, intraperitoneal administration   
Duration of Treatment: 
The target number of cycles is eight; 21 days per cycle, followed by a maximum of 3 months’ follow-up. 
On-going treatment with Cantrixil, beyond the planned 8 cycles of treatment scheduled in Parts A and B 


 
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of this study, is an option for patients who, based on the local Investigator’s opinion, are benefiting from 
treatment. All requests for continued access require discussion with the Sponsor. 
Endpoints 
Primary: 
1. Determination of the MTD of Cantrixil using standard safety monitoring assessments when 
administered as a monotherapy.  
2. Description of the PK of Cantrixil when administered as a monotherapy and in combination 
with standard chemotherapy agent(s). 
Secondary: 
1. PFS will be measured as the time from treatment start until objective disease progression as 
defined by RECIST version 1.1 and/or GCIG criteria.  
2. The time to paracentesis will be measured as the time from treatment initiation until the next 
paracentesis event for ascites.  
3. The volume of abdominal fluid will be measured by estimating the volume of malignant ascites 
drained at each paracentesis event. 
4. Disease response will be measured using RECIST version 1.1 criteria; during Follow-up, 
response may be also assessed using the Gynecological Cancer Intergroup (GCIG) response 
criteria that incorporates CA-125 measurements (see Appendix C). 
5. Concentration of CA-125 in peripheral blood will be assayed in local laboratories using locally 
validated assays at baseline and then weekly during treatment, at the End of Therapy and during 
Follow-up. 
Exploratory: 
1. Determination of the optimum dose and administration schedule (i.e. weekly vs twice weekly 
administration) using standard safety monitoring assessments, PK measurements and 
tolerability of delivery in the study centre. 
2. Enumeration of CETC in peripheral blood and malignant ascites (if present) will be assayed 
using the MAINTRAC® CETC Count method by Genostics or similar methodology.  
3. Clonogenicity of CETCs in peripheral blood and malignant ascites (if present) will be measured 
using the MAINTRAC® Tumour Sphere Units assay by Genostics or similar methodology. 
4. Expression of stem cell markers in the isolated colonies will be measured using fluorescein 
isothiocyanate-labelled (FITC-labelled) or alternatively labelled antibodies and scanning 
fluorescent microscopy techniques. 
Criteria for Evaluation 
Pharmacokinetics: 
Pharmacokinetic samples will be collected at the time points indicated in the proposed PK schedule for 
each subject: 
At each of the sampling periods a blood sample will be collected into a 4mL dipotassium 
ethyllenediaminetetraacetic acid (EDTA) tube and the sample processed to plasma. The plasma samples 
will be divided into a primary and back up sample and stored frozen at -80°C. The primary sample will 
subsequently be shipped to the contracted bioanalytical laboratory. The samples will subsequently be 
analysed for TRX-E-002-1 using a liquid chromatography tandem mass spectrometry (LC-MS/MS) 
based method which has been previously validated for determination of TRX-E-002-1 concentration in 


 
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human plasma. 
Efficacy: 
Although disease response is not the primary endpoint of this study, patients with measurable disease 
will be assessed for disease response by standard RECIST version 1.1 criteria. For the purposes of this 
study, patients should have their disease burden evaluated at baseline and re-evaluated every 6 weeks. 
Response and progression will be evaluated in this study using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumours (RECIST) committee, version 1.1; the Gynecological 
Cancer Intergroup (GCIG) response criteria that incorporates CA-125 measurements may also be used 
during Follow-up. As per RECIST version 1.1, the patient’s entire tumour burden will be documented at 
baseline and followed throughout the study as well as CA-125 levels. Only those patients that have 
received at least 1 cycle of chemotherapy, and have had at least 1 post-treatment disease evaluation, will 
be considered evaluable for disease response. 
Safety: 
Physical examination, vital signs, laboratory tests, including urinary analysis, 12-lead electrocardiograms 
(ECGs), and AE monitoring. 
Statistical Methods 
Determination of sample size: 
For this Phase I dose-escalation study to determine the MTD of Cantrixil as a monotherapy and to 
investigate the safety and tolerability when combined with standard chemotherapy, an appropriate 
sample size is not statistically determined.  
The dose-escalation Part A/Cycle 1 of the study is designed to determine the MTD of Cantrixil as a 
monotherapy in patients with ovarian cancer. The planned dose levels include 0.24, 0.6, 1.25, 2.5, 5, 10 
and 20 mg/kg. From the initial dose level, single patient cohorts will be used until an AE is observed 
during Part A/ Cycle 1 that meets the definition of a DLT or warrants further examination in the opinion 
of the Principal Investigator and the DSMC/B and then the dose escalation will follow the 3+3 dose 
escalation model to treat up to 3 to 6 patients at each escalating dose level. After Cycle 2, patients will 
continue at the same dose level combined with standard chemotherapy through Cycles 3 to 8 in Part A of 
the study. Patients who haven’t experienced a DLT but who do not complete Cycle 1 of therapy will be 
replaced. To establish the MTD in Part A of the study, up to 42 patients will be enrolled. An expanded 
cohort with 12 patients will be enrolled and treated at the MTD in Part B of the study.  
The total sample size may be up to 54 patients (up to 42 in Part A and 12 in Part B) enrolled into this 
study.   
Analysis populations:  
Maximum Tolerated Dose (MTD) population: The MTD population will include all patients who 
experienced DLTs in Cycle 1/Part A, and those who received all three weekly doses of study treatment 
in Cycle 1/Part A. The safety, tolerability and MTD data sets regarding the Cycle 1/Part A will be used 
to determine MTD from this analysis population.  
Safety (SAF) population: The SAF population will include all enrolled patients who receive at least one 
dose of study treatment. All safety analyses will be conducted on this population.  
Pharmacokinetic (PK) population: The PK population will include all SAF patients who have had at least 
one PK assessment. All PK analyses will be conducted on this population.   
Intent-to-Treat (ITT) population: The ITT population will include all enrolled patients who receive at 
least one dose of study treatment and from whom at least one post-baseline efficacy measurement is 
obtained. All efficacy analyses will be conducted on this population and will be based on the actual dose 


 
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level/single-weekly or twice weekly doses of Cantrixil at which each patient has been treated. 
Statistical Analysis: 
As appropriate, variables will be summarised descriptively (frequency and percent will be summarised 
for categorical variables; mean, standard deviation [SD], median, minimum, and maximum will be 
presented for continuous variables) by study visit and by treatment group, including dose group and 
monotherapy vs combination therapy. All study data will be listed by subject. 
MTD 
For determination of the MTD, individual subject data from the Part A/ Cycle 1 dose escalation part will 
be reported.  
In addition, for the final statistical analysis, the following will be analysed: 
• 
At each dose level, the number and proportion of subjects in the DLT population who 
experience a DLT during the first DLT evaluation period (Cycle 1/Part A). 
• 
At each dose level, the number and proportion of treatment-emergent AEs (TEAEs) 
experienced by subjects in the DLT population during the first DLT evaluation period 
(Cycle 1/Part A). 
The MTD will be determined according to the dose-escalation plan described above. 
The MTD is defined as the highest dose level at which no more than 1 subject out of 6 subjects treated in 
a cohort and evaluable for DLT determination experiences a DLT during Part A/ Cycle 1. 
Safety and tolerability 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
will be summarised by System Organ Class (SOC), Preferred Term, and dose cohort. Severity of AEs 
will be graded using the National Cancer Institute (NCI)-CTCAE version 4.03 severity grading scale. 
Adverse events will be further summarised by maximum severity and relationship to study medication.  
Prior and concomitant medications will be summarised by dose cohort. Standard chemotherapy 
medications will be separately summarised by dose cohort. Safety laboratory tests and vital signs 
assessments, will be summarised by treatment using statistics for continuous or categorical data, as 
appropriate.  
DLTs, safety and tolerability data will be summarised for Cycles 1 to 2 and Cycles 3 to 8 separately at 
MTD from Part A and Part B study, as appropriate. A detailed Statistical Analysis Plan (SAP) including 
dictionaries used for coding and software used will be finalised prior to clinical database lock of the 
study. 
Pharmacokinetic Parameters 
Summary statistics will be presented for Cantrixil (TRX-E-002-1) plasma concentrations at each 
scheduled time point by dose cohort (for example, mean, geometric mean, median, SD, standard error of 
the mean [SEM], coefficient of variation [CV] and range). Summary statistics will also be presented by 
dose cohort for all TRX-E-002-1 PK parameters, including  
• 
Area under the plasma concentration-time curve from time zero to the last quantifiable 
concentration (AUC0-last), 
• 
Maximum plasma concentration (Cmax) and 
• 
Time to maximum plasma concentration (tmax), plus if estimable:  
• 
Area under the plasma concentration-time curve from time zero extrapolated to infinity 
(AUC0-∞), 


 
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• 
Apparent terminal half-life (t1/2), 
• 
Clearance (CL) and  
• 
Volume of distribution (Vd).  
All concentrations below the limit of quantification and/or missing data will be labelled as such in the 
concentration data listings. Concentrations below the limit of quantification which are after Cmax will be 
treated as missing in summary statistics and for the calculation of PK parameters. Pharmacokinetic 
parameters will be determined by standard non-compartmental pharmacokinetic analyses using 
Phoenix 64 WinNonLin software. 
The PK assessment results will be described in a PK study report prepared by TetraQ at completion of 
the study. 


 
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3 LIST OF ABBREVIATIONS  
ADME 
Absorption, distribution, metabolism, and excretion 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical agent 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical (system) 
AUC 
Area under the plasma concentration-time curve 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
AUC0-last 
Area under the plasma concentration-time curve from time zero to 
the last quantifiable concentration 
BRCA 
Breast cancer susceptibility gene 
CA-125 
Cancer antigen 125 
CD44+ve 
Ovarian cancer stem-like cells 
CD44-ve 
Ovarian somatic cancer cells 
CETC 
Circulating epithelial tumour cell 
CI 
Confidence interval 
CL 
Clearance 
CSP 
Clinical study protocol 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
Cmax 
Maximum plasma concentration 
DBP 
Diastolic blood pressure 
DLT 
Dose limiting toxicity 
DSMC/B 
Data Safety Monitoring Committee/Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Cancer Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EU GMP 
European Union – Good Manufacturing Practice 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good manufacturing practice  
Hb 
Haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC50 
Median inhibitory concentration 


 
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ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IRB 
Internal Review Board 
ITT 
Intent to treat 
IV 
Intravenously 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry  
LDH 
Lactate dehydrogenase 
Max 
Maximum 
MedDRA 
Medical dictionary for regulatory activities 
Min 
Minimum 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NOAEL 
No observed adverse effect level 
NCI 
National Cancer Institute 
NOEL 
No Effect Level 
PK 
Pharmacokinetic 
OTC 
Over the counter 
PFS 
Progression Free Survival 
PT 
Prothrombin time 
QC 
Quality control 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
Serious adverse event 
SAF 
Safety (population) 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SBP 
Systolic blood pressure 
SEM 
Standard error of the means 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvate transaminase  
SOC 
System organ class 
STD10 
Severely toxic dose in 10% of rats tested 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Apparent terminal half life 
tmax 
Time to maximum plasma concentration 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
WHO-DD 
World Health Organization Drug Dictionary 


 
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4 INTRODUCTION   
4.1 Background Information 
Cantrixil is an investigational drug product consisting of the active ingredient, 
TRX-E-002-1, formulated in the cyclodextrin molecule, Dexolve-7. The active 
pharmaceutical ingredient, TRX-E-002-1, is the active enantiomer of a super-benzopyran 
molecule that has been identified as having potent anti-cancer activity against a broad 
range of cancer phenotypes. It has been selected particularly for its potent cytotoxicity 
against the two main sub-populations of ovarian cancer cells, namely ovarian cancer 
stem-like (CD44+ve) cells and ovarian somatic cancer (CD44-ve) cells. Against CD44-ve 
and CD44+ve cells, observed median inhibitory concentration (IC50) values for 
TRX-E-002-1 ranged from 23 to 109 nM.  
TRX-E-002-1 induces cell death by both caspase-dependent and caspase-independent 
apoptosis. The molecular target remains unconfirmed, but similar to other drugs of this 
class and based on in silico modelling, it may involve tumour-associated NADH oxidase 
(ENOX2) and disruptions to trans-membrane electron-transport mediated energy 
production (Brown et al., 2008). Recent mechanistic studies in ovarian cancer 
demonstrated that TRX-E-002-1 induces caspase-mediated apoptosis. All pro-apoptotic 
factors (Bax, bid, XIAP) were up-regulated along with significant up-regulation of pJun, 
suggesting activation of stress pathways associated with mitochondrial depolarisation. 
Akt was unaffected. 
The super-benzopyran family of drugs, including TRX-E-002-1, is derived from a family 
of naturally occurring plant diphenolic (benzopyran) compounds, (i.e., genistein and 
daidzein). Compounds such as genistein are plant hormones with pleiotropic 
characteristics in plants and can up- and down-regulate a range of enzymes and gene 
transcription factors. Similarly, benzopyrans have proven to have a wide range of 
pleiotropic effects in animals including humans and have been the subject of drug 
development programs across various cancer and degenerative disease indications. 
Pharmaceuticals in this class include Phenoxodiol, Triphendiol and two further 
investigational agents, ME-143 and ME-433. Starting with the first-in-class, Phenoxodiol, 
and ending with ME-433, these compounds demonstrate increasing potency in in vitro 
studies. Human clinical trials have successfully been completed for all of these agents 
over the last decade. No significant safety issues were identified with Phenoxodiol in over 
800 patients treated with the drug either orally or intravenously (IV) on a continuous basis 
for periods up to several years (Fotopoulou et al., 2014). However, the Phase III study for 
this agent failed due to a deficit in bioavailability of the oral formulation adopted 
(Fotopoulou et al., 2014). Triphendiol, selected because of its better bioavailability in 


 
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animals (Saif et al., 2009; Wang et al., 2011), was subjected to one Phase Ia clinical trial 
in Australia. This pharmacokinetic (PK) study showed that the compound underwent 
extensive liver metabolism in humans, producing a demethylated metabolite (ME-143) 
which in vitro studies found to be a significantly more potent anti-cancer agent.  
Commencing in 2009, Kazia Therapeutics Limited embarked on a drug discovery 
program seeking to achieve greater complexity of structure of its benzopyran drug 
technology platform. The progression in structural complexity from phenoxodiol, to 
triphendiol and then to ME-344 had resulted in progressive log-fold increases in anti-
cancer activity. Along with that increased potency came subtle changes in the molecular 
target, with phenoxodiol causing caspase-dependent apoptosis, triphendiol and ME-143 
causing both caspase-dependent and -independent apoptosis, and ME-344 killing cancer 
cells by catastrophic autophagy. 
A breakthrough in manufacturing technology, allowed the creation of benzopyrans of 
considerably greater complexity not previously possible, resulting in a new family of 
compounds with a 1 to 2 log-fold increase in anti-cancer potency compared to the earlier 
“simple” benzopyrans such as ME-344. This increase in anti-cancer potency is believed 
to come from an increase in the electron-transferring potential of the molecule, with both 
stronger electron donating and receiving activity. Such changes are well recognised as 
leading to stronger drug-target interactions. TRX-E-002-1 is the first of this 
“superbenzopyran” family of molecules to enter clinical research. 
 
4.1.1 Pre-Clinical Findings 
Cantrixil delivers a potent anti-cancer effect in a stringent mouse model of human ovarian 
cancer. The model is one where human CD44+ve cells are formed into spheroids and then 
injected intraperitoneally into athymic mice. This is a highly aggressive model where the 
spheroids form detectable tumours within 4 days in a disseminated manner throughout the 
abdomen. There is extensive tumour load and profound ascites by Day 20 without 
treatment requiring sacrifice of animals. In this model, Cantrixil injected intraperitoneally 
daily significantly reduces carcinomatosis, whereas cisplatin therapy produces a transient 
response, followed by rapid tumour recurrence. The anti-tumour effect has been 
demonstrated at doses of 50 and 100 mg/kg administered daily and also at 150 mg/kg 
administered three times a week. Cantrixil is non-irritant when dosed via the 
intraperitoneal route in this model. 
Cantrixil was also shown to be effective in a mouse model of recurrent 
chemotherapy-resistant ovarian cancer. In this model, mice were inoculated with human 
ovarian cells, tumours were allowed to establish, and the mice were then treated with 
standard chemotherapy (paclitaxel). While initially responding to chemotherapy, tumours 


 
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eventually recurred while still on therapy, thereby mimicking progressive chemo-resistant 
disease in women. In contrast to those mice treated with taxol, when mice with 
chemo-resistant tumours were treated with Cantrixil their growth was significantly 
inhibited. These data confirm that Cantrixil is active in a model of recurrent ovarian 
cancer where tumours are resistant to both cisplatin and paclitaxel and demonstrates the 
potential of Cantrixil for treating both therapy naïve and chemotherapy-resistant ovarian 
cancer in the clinic. 
Absorption, distribution, metabolism, and excretion (ADME) studies in healthy rats 
indicated that after intraperitoneal administration of a single dose of Cantrixil, 
TRX-E-002-1 had a relatively short half-life (time to maximum plasma concentration 
[tmax] = 0.5 to 2 hours and apparent terminal half-life [t1/2] = 2 to 3 hours) and was present 
in plasma and tissue predominantly in the parent, unconjugated form. High levels were 
observed in kidneys, pancreas, stomach, large intestine, adrenals, ovaries and skin 
although this was largely eliminated at 24 hours after exposure from all tissues except the 
large intestine. The drug was eliminated via both renal and hepatic routes in rats. A 
similar ADME profile was observed in dogs, except that it was cleared from the large 
intestine at 72 hours and while circulating TRX-E-002-1 was predominantly in the parent 
unconjugated form, it was conjugated in the tissues. In dogs and rats, following 14-day 
repeat exposure, there was no evidence indicating accumulation of TRX-E-002-1 with 
multiple dosing.  
Escalating dose studies indicated that the maximum tolerated dose (MTD) following a 
single dose of Cantrixil was 50 mg/kg in male and female rats. Based on a 28-day repeat 
dose and 14-day recovery study, the No Observed Adverse Effect Level (NOAEL) was 
observed to be 3 mg/kg for male rats and 10 mg/kg for female rats and the No Effect 
Level (NOEL) was 0.5 mg/kg for both male and female rats.  
Dogs appeared to tolerate higher doses of Cantrixil than rats, with single doses up to 
80 mg/kg being administered without obvious clinical signs of toxicity. The MTD for 
dogs was considered to be greater than 200 mg/kg for a single dose of Cantrixil. A 28-day 
repeat dosing study concluded that the NOAEL for male and female dogs together was 
10 mg/kg. In both species, there was a gender specificity in tolerance to Cantrixil.  
In both species (i.e., rats and dogs), clinical signs included lethargy, discoloured faeces, 
liquid/soft faeces, soft faeces and emesis. Necropsy and histological test article-related 
observations were most prominently seen in the gastrointestinal (GI) tract with red 
streaking a common observation. These GI toxicities resolved during the 14-day recovery 
period. Testis toxicity was also observed in both species with an effect on 
spermatogenesis and these effects did not completely resolve during the 14-day recovery 
period. Electrocardiogram (ECG) readings in dogs showed no effect of Cantrixil on the 
QT interval. Mild changes in blood pressure, heart rate and body temperature were 


 
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observed immediately following dosing but these parameters returned to normal within 
hours of dosing.  
Further information can be found in the Investigator’s Brochure (IB) (Cantrixil 
Investigator’s Brochure). 
4.2 Rationale  
Cantrixil is the first of this new “super” benzopyran drug family to reach the clinical 
research stage of development and is designed for intraperitoneal delivery. 
Pharmacokinetic studies have shown that intraperitoneal administration of chemotherapy 
results in a 10 to 20-fold higher drug exposure to tumours in the peritoneum than 
achieved with IV administration of chemotherapy. In addition, drugs administered to the 
peritoneal cavity have a significantly longer half-life than drugs given intravenously 
(Gourley et al., 2016). Based on the body of evidence in the literature (now 8 randomised 
clinical trials) (Jaaback et al., 2011), the National Cancer Institute (NCI) encourages the 
use of a combined IV and intraperitoneal chemotherapy regimen for ovarian cancer 
patients (Trimble and Alvarez 2006). Although intraperitoneal regimens resulted in 
higher rates of toxicity compared with IV, the evidence suggests that the benefits of 
intraperitoneal delivery outweigh the risk, with overall survival for women with advanced 
ovarian cancer extended by about 1 year (Walker 2013; Tewari et al., 2015). 
The unequivocal and reproducible efficacy of Cantrixil in mouse models of ovarian 
cancer and the relative tolerance of Cantrixil in both rodent and non-rodent animals, 
warrants further development of this drug candidate. The anti-tumour effect in a mouse 
model has been demonstrated at doses of 50 and 100 mg/kg administered daily and also at 
150 mg/kg administered three times a week. Cantrixil is non-irritant when dosed via the 
intraperitoneal route in this model. This Phase I study represents the next step in the 
clinical development program for Cantrixil. In this study, initially the drug will be 
delivered as a single agent in order to identify the MTD as a monotherapy. Safety and 
tolerability profiles of Cantrixil in humans will be investigated as well as the drug’s PK 
profile when delivered as a single agent. Once tolerance as a monotherapy has been 
established, the safety of Cantrixil as part of a combination therapy with standard 
chemotherapy agents will be examined. An initial assessment of the potential benefits of 
the drug will also be examined using tumour imaging and biomarkers to assess 
anti-cancer activity. 
The starting dose of Cantrixil of 0.24 mg/kg has been chosen based on the animal 
toxicology data. A common approach for many small molecules is to set the start dose at 
1/10 the severely toxic dose in 10% of the animals (STD 10) in rodents (Senderowicz, 
2010). In light of the good tolerance of this molecule in mice and dogs, as well as the 
MTDs determined in recent human clinical trials for related compounds (ME-344 and 


 
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ME-143; Bendell et al., 2014, Pant et al., 2014), the starting dose has been set at 1/10th 
the observed STD10 in rats. The human equivalent dose is 0.24 mg/kg, calculated using 
standard species conversion tables (FDA Guidance 2005) and adding a safety factor of 
10. This starting dose is around ten-fold less than the starting dose in humans for ME-143 
(2.5 mg/kg) and ME-344 (1.25mg/kg) (Bendell et al., 2014; Pant et al., 2014). 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practices (GCP) and applicable regulatory 
requirements. Aspects of the study concerned with the investigational medicinal 
product(s) (IMPs) will meet the requirements of European Union (EU) and Food and 
Drug Administration (FDA) Good Manufacturing Practices (GMP). 
4.3 Risk Assessment 
As this is the first study of Cantrixil in humans, there is no information on its PK and 
metabolism, safety or efficacy in a clinical setting. 
Non-clinical studies in rats and dogs have been undertaken. Some of the clinical signs 
observed in these studies included lethargy, swelling of the abdomen, discoloured faeces, 
liquid/soft faeces, and soft faeces. Necropsy and histological study drug-related 
observations were most prominently seen in the gastrointestinal tract and male 
reproductive organs. ECG readings in dogs showed no effect of Cantrixil on the QT 
interval. 
Preliminary data from experiments in human hepatic microsomes indicate that 
TRX-E-002-1 may inhibit cytochrome P450 drug metabolising enzymes, including 
CYP2C9, CYP2C8, CYP2C19, CYP2B6, CYP3A4, CYP2D6, CYP2A6 and CYP1A2. 
The results suggest that caution is warranted when administering Cantrixil with drugs 
metabolised by cytochrome P450 enzymes until further information is available. In 
particular, the potential interaction between Cantrixil and paclitaxel, a CYP2C9 substrate 
frequently used in the treatment of ovarian cancer, needs to be considered. It should also 
be noted that given the toxicity observed in male reproductive organs and spermatozoa, 
males should initially be excluded from this Phase I study. Other study drug-related 
effects were predominantly associated with the gastrointestinal tract, specifically nausea, 
emesis and diarrhoea. 
4.4 Urgent safety measures 
The Sponsor and Investigator may take appropriate urgent safety measures in order to 
protect the patients of a clinical trial against any immediate hazard to their health or 
safety. If such measures are taken the Sponsor shall immediately (no later than 3 days 
from the date the measures are taken) give written notice to the licensing authority and 
the relevant Ethics Committee of the measures taken and the circumstances giving rise to 
those measures. 


 
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The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
5 STUDY OBJECTIVES 
5.1 Primary Objectives 
• To determine the MTD of Cantrixil when delivered as a single agent, administered 
intraperitoneally, at a weekly administration frequency.  
• To evaluate the safety and tolerability of Cantrixil delivered via intraperitoneal 
administration as a single agent and in combination with standard chemotherapy, 
when administered weekly. 
• To characterise the PK of intraperitoneal Cantrixil when delivered as a single 
agent and in combination with standard chemotherapy. 
5.2 Secondary Objectives 
• To evaluate the progression free survival (PFS). 
• To evaluate the time to paracentesis and the volume of malignant ascites drained 
at each paracentesis event (for those patients with malignant ascites). 
• To evaluate the potential anti-cancer activity of Cantrixil using Response 
Evaluation Criteria in Solid Tumours (RECIST) criteria, version 1.1 and CA-125 
measurements. 
• To evaluate the change in cancer antigen 125 (CA-125) in peripheral blood before 
and after treatment with Cantrixil. 
5.3 Exploratory Objectives 
• To evaluate the safety, tolerability, PK, and activity of Cantrixil when 
administered intraperitoneally as a single agent and in combination at a twice 
weekly administration frequency 
• To evaluate the change in the number of circulating epithelial tumour cells 
(CETCs) in peripheral blood and malignant ascites (if present) before and after 
treatment with Cantrixil. 
• To evaluate the clonogenicity of CETCs in peripheral blood and malignant ascites 
(if present) before and after treatment with Cantrixil. 
• To evaluate the expression of stem cell markers, CD44 and ALDH, in colonies 
isolated in the clonogenicity assays. 
 


 
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6 INVESTIGATIONAL PLAN 
6.1 Overall Study Design 
This study is a progressive design with 3 discrete Parts (Part A: Dose escalation and Part 
B: Dose expansion). The overall study schema is presented in Figure 1.  
Cycle 1/Part A is a dose-finding assessment (dose escalation) to establish the MTD of 
Cantrixil when administered as a single dose once a week for 3 weeks. Cycle 2/Part A 
continues with 3 additional weekly doses of Cantrixil as a monotherapy before an 
assessment of disease response. In Cycles 3 to 8/Part A patients will be administered the 
same once-weekly dose of Cantrixil they tolerated in Cycles 1 and 2 (tolerance defined as 
no dose limiting toxicities [DLTs] or unacceptable adverse events [AEs]) in combination 
with a standard chemotherapy agent, in order to assess the safety and tolerability of 
Cantrixil in combination therapy. Standard chemotherapy drugs will be administered at 
the standard efficacious doses to maintain optimum benefit of known drug combinations 
for patients. Treating physicians may choose the combination therapy from the list in 
Table 1 taking into consideration factors such as pre-existing comorbidities, prior 
toxicities and responses as well as patient and physician preferences. 
 
Table 1 Permitted Combination Therapies 
Regimen  
Reference 
Carboplatin AUC 4 over 1 h on Day 4 every 21 d for six cycles 
Dizon et al., 2015 
Liposomal doxorubicin 40-50 mg/m 2 IV over 30 min on Day 4 every 
21 d  
Gordon et al., 2004 
Gemcitabine 1000 mg/m² IV over 30 min on Days 4 and 11 (Parts A 
and B); every 21 d  
Markman et al., 2003 
Paclitaxel 80 mg/m 2 IV over 1 h weekly on Days 4, 11 and 18 (Parts A 
and B)  
Markman et al., 2006 
Docetaxel 75-100 mg/m 2 IV over 1 h on Day 4 every 21 d 
Rose et al., 2003 
Topotecan 4.0 mg/m2 on Days 4, 11 and 18 every 21 d 
Sehouli et al. 2011 
Best supportive care and extended monotherapy with Cantrixil alone 
 
 
Combination chemotherapy may not be administered until 24 hours after administration 
of Cantrixil to avoid any adverse drug-drug interactions. All combination therapies and 
concomitant medications must be diligently recorded in the patients’ electronic case 
report form (eCRF).  
Once the MTD has been determined in Part A/Cycle 1, an additional 12 patients will be 
recruited in an expansion cohort for Part B. These patients will receive 2 cycles of 
Cantrixil monotherapy at the MTD, followed by up to 6 cycles of combination therapy.  


 
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Patients enrolled into the respective parts of the study may not receive treatments under 
different parts of the protocol e.g., if a patient enters Part A, she may not also continue to 
Part B even if she considered to have completed Part A. 
To accommodate the intraperitoneal administration of Cantrixil, an in-dwelling, closed 
catheter or port will be inserted if the patient does not already have one. For 
intraperitoneal ports, the minimum period between port placement and the first 
administration of Cantrixil must not be shorter than 7 days. For other intraperitoneal 
access devices, the period may be shorter if adequate stability and/or healing of the 
delivery system’s insertion site is confirmed by the treating physician. 
Patients should begin protocol treatment within a maximum of 28 days of enrolment (i.e., 
signing of consent form). 
Patients will start at Dose Level 0 (see Table 2) which is calculated to be the human 
equivalent of 10% of the STD10 dose in rats (dose is 1/10 the severely toxic dose in 10% 
of rats tested). Single patient cohorts will be treated with increasing doses of Cantrixil 
until an AE is observed during Part A/Cycle 1 that meets the definition of a DLT or, in 
the opinion of the Data Safety Monitoring Committee/Board (DSMC/B) and the 
Investigator, warrants observing additional patients at this dose level; at this point the 
study will revert to a 3+3 rules-based dose escalation study (see Section 6.1.2). The 
decision to expand from single patient cohorts to 3 patient cohorts is critical for the safety 
of participants and will be made with input from the Investigator and DSMC/B 
responsible for this study (see Section 6.1.1). Dose levels -1 and -2 will only be activated 
if there are 2 DLTs at Dose Level 0 and -1, respectively. Once the study enters a 3+3 
rules-based design, the study will not revert back to single patient cohorts. 
Table 2 
Doses at each Dose Level 
Dose Level 
Cantrixil 
Patient Number 
Level -2 
0.06 mg/kg  
Dose is half of Level -1 
n = 2 to 6 
Level -1 
0.12 mg/kg  
Dose is half of Level 0 
n = 2 to 6 
Starting dose: 
Level 0 
0.24 mg/kg  
Dose is equivalent to 10% of STD10 
n = 1 to 6 
Level 1 
0.6 mg/kg  
Dose is 2.5 x Dose Level 0 
n = 1 to 6 
Level 2 
1.25 mg/kg  
Dose is 2.1 x Dose Level 1 
n = 1 to 6 
Level 3 
2.5 mg/kg  
Dose is 2 x Dose Level 2 
n = 1 to 6 
Level 4 
5.0 mg/kg  
Dose is 2 x Dose Level 3 
n = 1 to 6 
Level 5 
10.0 mg/kg  
Dose is 2 x Dose Level 4 
n = 1 to 6 


 
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Level 6 
20.0 mg/kg  
Maximum dose to test 
n = 1 to 6 
STD10: Severely toxic dose in 10% of rats tested 
If any of the following unacceptable AEs or DLTs are observed and unless clearly 
unrelated to study treatment (e.g., disease progression), treatment at the currently 
allocated Cantrixil dose will be be paused. At this point a dose reduction may be 
considered or the treatment may be terminated, depending on what is considered by the 
investigator to be in the participant’s best interest. 
• Hematologic toxicity 
o Grade 4 neutropenia, lasting at least 5 days, 
o Grade 3 or Grade 4 neutropenia associated with fever >38.5°C,  
o Grade 4 thrombocytopenia lasting at least 5 days,  
o Grade 3 thrombocytopenia associated with severe bleeding in the opinion 
of the Investigator, 
o Dose delay of ≥3 weeks due to failure to recover counts. 
• Any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
Grade 3 or Grade 4 non-haematological toxicity except: 
o Alopecia, 
o Grade 3 abdominal pain deemed related to the port or catheter as 
determined by the treating physician, 
o Grade 3 anorexia, 
o Grade 3 fatigue, 
o Grade 3 nausea and/or vomiting, or diarrhoea, lasting ≤48 hours with or 
without maximal medical management, 
o Grade 3 dehydration as a result of nausea and vomiting, 
o Grade 3 constipation, 
o Grade 3 metabolic abnormalities [hypokalaemia, hypomagnesemia, 
hypocalcaemia, hypophosphatemia]) that recovers to Grade 1 or less 
within 48 hours with or without medical management, 
• Other serious adverse events which, in the opinion of the treating investigator, 
necessitate temporary or permanent cessation of administration, 
• 
Treatment delays of ≥3 weeks due to any non-haematological toxicity will 
constitute a DLT. 


 
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If any unacceptable AE or DLT is observed in any cycle, patients may be dose reduced to 
the next lower dose level of Cantrixil for subsequent doses of therapy. If a second 
unacceptable AE or DLT is observed during any cycle within the same patient, treatment 
with Cantrixil will be discontinued. Investigators may continue with the standard 
chemotherapy at their discretion and if it is considered safe and in the patient’s best 
interest. 
All patients who discontinue from the study treatment (i.e. are now Off Therapy/End of 
Therapy) will progress to follow-up unless the patient withdraws consent.  
The initiation of each new cycle of Cantrixil will be at the discretion of the Investigator 
and will depend on the potential or measurable benefit to the patient assuming continued 
tolerability and adequate organ function. 
Cantrixil treatment will also be stopped due to RECIST version 1.1 defined disease 
progression observed after at least 2 cycles of combination therapy, or patient consent 
withdrawal. Note that patients with progressive disease at the end of 2 cycles of Cantrixil 
monotherapy will not be taken off therapy if Cantrixil has been well-tolerated. 
Pre-clinical data would suggest that the maximum benefit of Cantrixil will be realised as a 
combination therapy, hence all patients will have the opportunity to continue receiving 
Cantrixil as a combination therapy. Additionally, patients receiving combination therapy 
that are observed to have progressive disease as identified by RECIST version 1.1 criteria 
but who, in the opinion of the Investigator, continue to derive clinical benefit, may 
continue treatment. Patients may also be discontinued from study treatment if the 
Investigator considers continuing therapy is not in the patient’s best interest.  
All patients discontinued from study treatment (i.e. are now Off Therapy/End of Therapy) 
will progress to follow-up unless the patient withdraws consent.  
Tumour assessment via radiological imaging will be conducted during screening and 
every 6 weeks, i.e., at the end of monotherapy and then after every 2 cycles of 
combination therapy. The screening period is up to 28 days before the Cycle 1 Day 1 dose 
of Cantrixil. Either contrast-enhanced magnetic resonance imaging (MRI) or contrast-
enhanced computed tomography (CT) may be used, but once a modality is used at 
baseline this must be used consistently for that patient throughout their participation on 
the study. Other imaging is not mandatory, but may be performed if clinically indicated.  
Adverse events will be monitored for the duration of the study from the time of informed 
consent. Blood samples will be collected weekly for standard safety testing, or more 
frequently if clinically relevant, during the study. Additional volumes of blood will be 
collected before and after administration of Cantrixil for PK analysis (4 mL per time point 
as per the proposed PK schedule [Table 5] and for any exploratory studies (at baseline, 
end of Cycles 2, and End of Therapy - 15 to 20 mL at each time-point). 


 
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Part A (Dose escalation of Cantrixil as a monotherapy):  
Cycle 1  
Following placement of a port or catheter, eligible patients will be administered a single 
intraperitoneal dose of the study treatment Cantrixil (TRX-E-002-1 formulated in 
Dexolve-7) once a week for 3 weeks. Patients will be monitored for DLTs over the 
21-day cycle (Cycle 1).  
Blood samples will be collected weekly at each scheduled visit for standard safety testing, 
or more frequently if clinically relevant. Results of the safety assessments must be 
available prior to Cantrixil administration to ensure that all assessments still meet the 
inclusion criteria as described in Section 6.2.1 and it is safe to proceed to the next dose of 
treatment. Treatment delays of up to three weeks are allowed for recovery without being 
classified as a protocol deviation or a dose limiting toxicity. 
Patients will continue to be monitored until they meet the off-study criteria (see below) 
but will only be evaluable for DLTs that define the MTD of Cantrixil as a monotherapy 
during Cycle 1/Part A.  
Patients will start at Dose Level 0 (see Table 2) which is calculated to be the human 
equivalent of 10% of the STD10 dose in rats (dose is 1/10 the severely toxic dose in 10% 
of rats tested). Single patient cohorts will be treated with increasing doses of Cantrixil 
until an AE is observed during Part A/Cycle 1 that meets the definition of a DLT or, in 
the opinion of the DSMC/B and the Investigator, warrants observing additional patients at 
this dose level; at this point the study will revert to a 3+3 rules-based dose escalation 
study (see Section 6.1.2). The decision to expand from single patient cohorts to 3 patient 
cohorts is critical for the safety of participants and will be made with input from the 
Investigator and DSMC/B responsible for this study (see Section 6.1.1). Dose levels -1 
and -2 will only be activated if there are 2 DLTs at Dose Level 0 and -1, respectively. 
Cycle 2 
Patients that are still on study treatment at the end of Cycle 1/Part A will receive another 
cycle of Cantrixil monotherapy with once weekly dosing before disease assessment. Note 
that a disease assessment will be conducted at the end of monotherapy but patients will 
not automatically be removed from therapy at this time-point if they have progressive 
disease as defined by RECIST version 1.1 criteria. This is because the pre-clinical data 
strongly suggests that the benefit of Cantrixil will most likely be realised as a 
combination therapy. All patients will, therefore, have the opportunity to progress to a 
combination therapy with Cantrixil. 
Patients that have not discontinued from the study at the end of Cycle 2 will proceed to 
Cycles 3 to 8/Part A of the study.  


 
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Cycles 3 to 8 (Cantrixil in Combination with Standard Chemotherapy) 
Patients that progress to Cycles 3 to 8/Part A will continue on the same dose level of 
Cantrixil that they tolerated in Cycles 1 and 2/Part A but in combination with a systemic 
chemotherapy selected from Table 1 for the patient by the treating physician/Investigator. 
In the rare event that there does not exist a combination chemotherapy that could be 
recommended by the Investigator, patients may continue to Cycles 3 to 8 receiving 
Cantrixil as a monotherapy if it is deemed by the Investigator and the patient to be 
providing potential benefit as a monotherapy.  
During Cycles 3 to 8/Part A, patients will be administered Cantrixil once per week for 
each 21-day cycle. The combination chemotherapy will be administered as per the 
schedules in Table 1. Before administration of the combination chemotherapy, the PK 
results for each patient from Part A/ Cycle 1 will be reviewed by the DSMC to ensure that 
the PK profile of Cantrixil is indeed compatible with the proposed schedule for the 
combination chemotherapy agent. 
With the anticipated PK profile of Cantrixil, there should be a 24-hour window after each 
dose of Cantrixil before any other chemotherapy agent is administered to avoid any drug-
drug interactions. All combination therapies and concomitant medications must be 
diligently recorded in the patient’s eCRF.   
Part B (Expansion Cohort at MTD): 
Once the MTD has been established in Part A/Cycle 1, an expansion cohort will be 
recruited at the MTD. An additional 12 patients will be recruited in this cohort on top of 
those recruited in Part A at the MTD. These patients will be subjected to the same 
intervention described above with 2 cycles of monotherapy followed by up to 6 cycles of 
combination therapy. 
Continued Access for Patients: 
All patients who complete eight cycles, and in whom the local Investigator feels there has 
been a clinical benefit from treatment, may continue to receive Cantrixil, following 
discussion with the Sponsor. Those patients granted continued access will be dosed 
weekly with Cantrixil at the dose that they have been receiving during cycles 1 to 8. 
Patients will be monitored and supported as per local standard of care procedures, 
including any blood and urine safety assessments and on-going radiology assessments. 
During this period of extended access, Kazia will only collect data on adverse events, 
Cantrixil administration and drug accountability. Cantrixil treatment will be stopped due 
to locally defined disease progression, recurrence of an unacceptable toxicity after 1 
Cantrixil dose reduction or patient consent withdrawal. The definition of unacceptable 
toxicity during this extended access period is the same as defined in section 6.1.3. 
Patients may also be discontinued from study treatment if the Investigator considers 


 
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continuing therapy is not in the patient’s best interest. When dosing of Cantrixil is 
discontinued, the Off Therapy/End of Therapy schedule of assessments in Table 4 should 
be conducted. All patients discontinued from study treatment (i.e. are now Off Therapy/ 
End of Therapy) will progress to follow-up unless the patient withdraws consent.  
It is at the discretion of the Investigator whether this continued treatment is a maintenance 
monotherapy or a combination chemotherapy.  
All patients that are provided continued access to Cantrixil must agree to on-going data 
collection for monitoring safety, progression and survival. 
. 


 
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Figure 1 
Proposed Dosing Schema 
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Car
Dox
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Day
Week
Topotecan 4.0 mg/m2 IV over 1 h on Days 4, 11 and 18 (Part A and B)
Doc
Green arrow indicates visit includes full safety assessment before administration of therapy, as 
per table of assessments
Blue arrows represent visits where only the collection of 24-hour PK blood samples occurs; only 
in certain cycyles, see PK collection schema. 
Red arrow indicates visit includes a full safety assessment PLUS a decision to continue to next 
cycle based on tolerability and potential benefit. Day 22 may coincide with Day 1 of the next 
cycle. A tumour assessment may be conducted on this day as per the schedule of assessments. 
Purple arrow indicates that a visit may be scheduled for the administration of the combination 
chemotherapy. A visit will be scheduled if a coloured box appears in the column for the 
combination chemotherapy that has been selected for the patient.
Dose of Cantrixil administered IP according to starting dose allocated upon enrolment. Cantrixil 
is administered once weekly on Days 1, 8 and 15 for Parts A and B. The dose that any individual 
patient receives will not be escalated; it will either remain the same as the starting dose or may 
be de-escalated by one dose level. 
Combination therapy options and scheduling are described below (weeks 3 - 8). Ctx may be continued as a 
monotherapy or in combination with one of the below chemotherapeutic options. The decision to progress to 
combination and the chemotherapy added to treatment will be decided by the treating physician. The shading color 
below is repeated in the table above to indicate days on which visits will be required to follow an appropriate 
treatment schedule. In all options, the black arrow indicates continued weekly Cantrixil treatment. 
Carboplatin AUC4 over 1 hour on Day 4 (Part A and B) 
Liposomal Doxorubicin 40 - 50 mg/m2 IV over 30 min on Day 4 (Part A and B) 
Gemcitabine 1000 mg/m2 IV over 30 min on Days 4 and 11 (Part A and B) 
Paclitaxel 80 mg/m2 IV over 1 h weekly on Days 4, 11, and 18 (Part A and B) 
Ctx ()
Topo
3 to 8
Gem
Pac
Week
1
2
3



Doc+ Ctx
Gem + Ctx
Pac+ Ctx
Docetaxel 75 - 100 mg/m2 IV over 1 h on Day 4 (Part A and B) 
Cycle 
1 to 2
2
NVGN-002-101 Study Schema

1
Ctx
Visit
Part A and Part B
Day
Visit
Cycle 
Car + Ctx
Dox + Ctx
Topo+ Ctx
Ctx
 


 
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6.1.1 Data Safety Monitoring Committee/Board 
This study will utilise a Data Safety Monitoring Committee/Board (DSMC/B) throughout 
the study. The membership and governance of this committee are outlined in a separate 
charter. The DSMC/B will review safety data from each patient at the end of each Part 
A/Cycle 1 to confirm that it is safe to dose escalate and to assess the compatibility of the 
proposed combination therapy schedule. Written confirmation from the DSMC/B will be 
required before a patient can be administered a higher dose than the previously enrolled 
patient or proceed to combination therapy. 
An appropriate interval will separate the investigation of dose levels to permit a timely 
review and evaluation of safety, tolerability and PK data prior to proceeding to a higher 
dose level.  
All data reviewed at the DSMC/B meeting (safety, tolerability and PK where appropriate) 
will be subjected to a quality control (QC) review.  
The DSMC/B will continue to assess safety data throughout the course of the study, and 
may discontinue patient exposure to particular combinations if evidence of unacceptable 
toxicity emerges. 
 
6.1.2 Dose Escalation Criteria 
Single patient cohorts will be treated with increasing doses of Cantrixil until a treated 
patient exhibits an AE during Part A/Cycle 1 that meets the definition of a DLT or, in the 
opinion of the Investigator and the DSMC/B, warrants observing additional patients at 
this dose level; at this point the study will revert to a 3+3 rules-based dose escalation 
design (see Table 3). During the single patient cohort stages and the 3+3 design, once the 
single patient or the first 3 patients at a dose level have completed Cycle 1/Part A, 
tolerability data will be evaluated by the DSMC/B and a decision to escalate to the next 
dose level will be made. Once the study enters a 3+3 rules-based design, the study will 
not revert back to single patient cohorts. 


 
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Table 3 
3+3 Design Dose-escalation Plan  
Number of patients with 
DLT at a given dose level 
Action 
0 out of 3 
Enter at least 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level and 
• 
if 0 of these 3 new patients experiences a DLT, proceed to the 
next dose level; 
• 
if ≥1 of this group suffer a DLT (for a total of ≥2/6 patients with 
a DLT), this dose exceeds the MTD and dose escalation is 
stopped. To further assess tolerability, 3 additional patients will 
be entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. Upon determination of the MTD, 
the study will proceed to Part B of the study. 
≥2 
Dose escalation will be stopped. This dose exceeds the MTD. To further 
assess tolerability, 3 additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at that dose and the 
study will proceed to Part B of the study. 
DLT: Dose limiting toxicity; MTD: maximum tolerated dose 
Progression to the next higher dose level will be stopped if one or more patients 
experience a DLT (as outlined in Table 3) but also if an AE occurs that, in the opinion of 
the Investigator or Sponsor’s medical representative and the DSMC/B, warrants 
discontinuation of dose escalation. 
 
6.1.3 Study Stopping Rules 
Dosing for any individual patient will be stopped if the patient experiences a SAE or an 
AE, which in the opinion of the Investigator or Sponsor’s medical representative or 
DSMC/B, warrants discontinuation of the study treatment for that patient’s wellbeing.  
If any of the following unacceptable AEs or DLTs are observed and unless clearly 
unrelated to study treatment (e.g., disease progression), treatment at the currently 
allocated Cantrixil dose will be paused. At this point a dose reduction may be considered 
or the treatment may be terminated, depending on what is considered by the investigator 
to be in the participant’s best interest.: 
  
• Hematologic toxicity 
o Grade 4 neutropenia, lasting at least 5 days, 
o Grade 3 or Grade 4 neutropenia associated with fever >38.5°C,  
o Grade 4 thrombocytopenia lasting at least 5 days,  


 
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o Grade 3 thrombocytopenia associated with severe bleeding in the opinion 
of the Investigator, 
o Dose delay of ≥3 weeks due to failure to recover counts to levels described 
in the study inclusion criteria as described in Section 6.2.1. 
• Any CTCAE version 4.03 Grade 3 or Grade 4 non-haematological toxicity except: 
o Alopecia, 
o Grade 3 abdominal pain deemed related to the port or catheter as 
determined by the treating physician, 
o Grade 3 anorexia, 
o Grade 3 fatigue, 
o Grade 3 nausea and/or vomiting, or diarrhoea, lasting ≤48 hours with or 
without maximal medical management, 
o Grade 3 dehydration because of nausea and vomiting, 
o Grade 3 constipation, 
o Grade 3 metabolic abnormalities [hypokalaemia, hypomagnesemia, 
hypocalcaemia, hypophosphatemia]) that recovers to Grade 1 or less 
within 48 hours with or without medical management, 
• Other serious adverse events which, in the opinion of the treating investigator, 
necessitate temporary or permanent cessation of administration, 
• Treatment delays of ≥3 weeks due to any non-haematological toxicity will 
constitute a DLT. 
All patients who discontinue from the study treatment (i.e. are now Off Therapy/End of 
Therapy will progress to follow-up unless the patient withdraws consent.  
The occurrence of significant safety events as described above will require that further 
dosing of other patients be evaluated by the Investigator or Sponsor’s medical 
representative to determine study discontinuation. 
6.1.4 Discussion of Study Design 
Current literature on Phase I dose-escalation designs suggests that when the pre-clinical 
data indicate a wide therapeutic window and little expected toxicity in human patients, it 
is very reasonable to apply an aggressive dose titration (e.g., by using an accelerated 
titration design or Bayesian-based methods) (Le Tourneau et al., 2009). However, if the 
pre-clinical data were less certain about how human patients will tolerate the drug or 
predict a very narrow therapeutic window, then it would be prudent to choose a more 


 
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conservative dose escalation scheme (Le Tourneau et al., 2009). Given the good 
tolerability of this class of drugs in humans as demonstrated in the clinical trials using 
Phenoxodiol, ME-143 and ME-344 (Saif et al., 2009, Pant et al., 2014) and the excellent 
tolerability of Cantrixil in mice and dogs, this study will adopt a dose escalation scheme 
that is accelerated compared to the traditional Fibonacci sequence but starts at the 
conservative 10% of STD10 level.   
 
6.2 Study Population 
Patients with any stage of persistent or recurrent ovarian cancer, fallopian tube cancer or 
primary peritoneal cancer will be enrolled into this study provided that they satisfy the 
following inclusion/exclusion criteria. 
6.2.1 Subject Inclusion Criteria 
For inclusion in the study, patients have to fulfil all of the following criteria: 
1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer. The original diagnosis must be verified by a histology 
report. All histological sub-types and all grades of disease are eligible to 
participate; grade, histological sub-type and breast cancer susceptibility gene 
(BRCA) status must be recorded at study entry. 
2. Patients must be female and at least 18 years old. Patients may be women of child-
bearing potential as long as they are not pregnant or breast-feeding and able to 
adopt adequate contraception as described in section 6.2.3.1 
3. Patients with malignant ascites are eligible to participate; paracentesis will be 
conducted before the administration of Cantrixil. Drainage of the maximum 
volume of ascites should be performed according to local standard operating 
procedures before administration of Cantrixil. 
4. Patients must have completed at least two (2) or more prior regimens (including 
adjuvant therapy) for their ovarian, Fallopian tube or primary peritoneal cancer 
prior to participation in the current study; all prior therapies must be recorded at 
baseline. Patients that have received prior intraperitoneal therapy are eligible for 
this study. Patients should have failed standard of care drugs prior to being 
eligible to be part of the proposed study. 
5. Patients must have platinum-resistant relapsed disease, platinum refractory 
disease, or have documented intolerance to platinum therapy. Patients will not be 
eligible based on rising CA-125 levels alone, patients must have other clinical 
symptoms (such as malignant ascites) or radiological tumour measurements 
that support disease recurrence or progression. 


 
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6. At least 4 weeks must have passed from any previous therapy (6 weeks for 
bevacizumab, nitrosoureas or mitomycin C treatment) any toxicities from prior 
therapies must have resolved to less than or equal to CTCAE version 4.03 Grade 1 
with the exception of alopecia, Grade 2 prior platinum-therapy related neuropathy 
and Grade 2 anaemia.  
7. Patients must have a performance status of Eastern Cooperative Oncology Group 
(ECOG) 0 to 2 and, in the Investigator’s opinion, be able to complete at least a 
major part of the study. 
8. Patients willing and able to undergo insertion of a port or catheter for 
intraperitoneal access; the type of port or catheter used will be at the discretion of 
the Investigator and will be recorded. 
9. Patients with measurable or non-measurable disease may be enrolled; disease 
response will be measured according to RECIST version 1.1 criteria using contrast 
CT or MRI and CA-125 measurements. 
10. Patients with acceptable hepatic and marrow function as defined below: 
• 
Absolute neutrophil count >1.5 x 109/L without myeloid growth factor 
support. 
• 
Platelets >100 x 109/L. 
• 
Total bilirubin; <2.5 times the institutional upper limit of normal (ULN). 
• 
Haemoglobin (Hb) of >10 g/dL; patients with Hb >9g/dL will be considered 
for this study if they have not received a transfusion or other bone marrow 
support. Patients with Hb >10 g/dL that have received a recent transfusion 
will only be eligible if there has been a wash-out period of 7 days for rhesus 
factor and 10 days for platelet transfusions, respectively.  
• 
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvate 
transaminase [SGPT]) ≤2.5 x institutional ULN if no demonstrable liver 
metastases or <5 x ULN in the presence of liver metastases.  
• 
Serum creatinine <1.5 x ULN. 
• 
Prothrombin time (PT) or international normalised ratio (INR) ≤1.5 x ULN 
and activated partial thromboplastin time (aPTT) ≤1.5 x ULN if not on 
anticoagulation treatment. 


 
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11. Patients willing and able to comply with all study requirements, including 
treatment timing and/or nature of required assessments and treatment at 
designated study centre. 
12. Each participant must be adequately informed about the purpose of the study; 
potential benefits and risks; their right to refuse participation or to withdraw 
consent at any time; institutional affiliation and potential competing interests of 
the researcher; and sources of study funding and have signed and dated a written 
informed consent form. 
6.2.2 Subject Exclusion Criteria 
Any of the following is to be regarded as a criterion for exclusion from the study: 
1. Patients who have had chemotherapy, targeted therapies, biologic therapy, 
immunotherapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C or bevacizumab) prior to entering the study. 
2. Patients must not have had major surgery within 4 weeks prior to screening. 
3. Patients may not have received any other investigational medicinal products 
(IMPs) or participated in any other interventional clinical research studies within 4 
weeks of the first Cantrixil administration. 
4. Patients receiving any medications or substances that are strong inhibitors or 
inducers of cytochrome P450 (CYP)1A2, CYP2B6 and CYP3A4 or those 
substances with narrow therapeutic index are not to be enrolled. These compounds 
are prohibited from screening until completion of end of therapy or first post-
treatment follow-up visit. For a list of prohibited medications see the University of 
Indiana Clinical Pharmacology Department's P450 Drug Interaction Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/). Note: the use of paclitaxel 
is allowed, but only 24 hours after Cantrixil administration. 
5. Patients deemed by the investigator to be at high risk of bowel perforation or 
obstruction are excluded, including but not limited to any one or more of the 
following;  
• 
Patients with a recent history (previous 12 months) of bowel obstruction prior 
to study entry.  
• 
Patients with CT scans that suggest invasion of bowel by tumour. 
• 
Patients with symptoms to suggest impending bowel obstruction.  
• 
Patients with prior whole abdominal radiotherapy. 


 
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• 
Patients with chronic inflammatory bowel diseases such as Crohn's disease or 
ulcerative colitis. 
6. Patients may not have uncontrolled or severe systemic diseases or psychiatric 
conditions, which in the Investigator’s opinion makes it unsafe for the patient to 
participate in the study or would hinder compliance with the protocol. Screening 
for chronic conditions is not required. 
7. Patients who are pregnant, lactating, or unable to adopt adequate contraception; 
women of childbearing potential must have a negative pregnancy test within 
7 days prior to screening. 
8. Patients with active hepatitis B or C.   
9. Patients known to have tested positive for human immunodeficiency virus (HIV). 
10. Patients with a known hypersensitivity to or a serious reaction to benzopyrans are 
excluded. 
6.2.3 Restrictions 
• All medications, both prescription and over-the-counter (OTC), taken within 
30 days of the study screening must be reported and recorded on the eCRF. 
• Grapefruit and grapefruit juice are prohibited, from 1 week prior to the start of the 
study (Day 1) until the last PK sample has been collected. 
• Use of medications or substances that are strong inhibitors or inducers of 
cytochrome P450 (CYP)1A2, CYP2B6 and CYP3A4 or those substances with 
narrow therapeutic index are prohibited from screening until completion of end of 
therapy or first post-treatment follow-up visit. For a list of prohibited medications 
see the University of Indiana Clinical Pharmacology Department's P450 Drug 
Interaction Table (http://medicine.iupui.edu/clinpharm/ddis/main-table/). Note: 
the use of paclitaxel is allowed, but only 24 hours after Cantrixil administration. 
• Medications which are moderate to weak P450 enzyme inducers or inhibitors (see 
list referenced above), should have a complete washout prior to Cantrixil 
administration and only be administered 24 hours after Cantrixil administration. 
These medications should be used with caution and the Investigator should be 
alert for any potential unpredictable drug-drug interactions. 


 
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6.2.3.1 Avoidance of Pregnancy 
Women of Childbearing Potential 
Pregnancy should be avoided by either true abstinence or the use two effective means of 
contraception (see Section 6.2.3.2) for the duration of the study and a total period of 
3 months after the patient has taken the last dose of Cantrixil. 
In order to include women of childbearing potential in any clinical trial, certain 
precautions pertaining to pregnancy must be taken. These will include pregnancy testing 
at screening, at the start of each cycle, and follow-up.  
Female patients who become pregnant during the study will be withdrawn. 
Women of Non-Childbearing Potential 
Female patients of non-childbearing potential are defined as; no menses for 12 months 
without an alternative medical cause, a hysterectomy within the last 12 months, bilateral 
tubal occlusion/ligation and bilateral oophorectomy. A high follicle stimulating hormone 
(FSH) level in the post-menopausal range may be used to confirm a post-menopausal 
state in women not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
6.2.3.2 Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those which result in a low 
failure rate (i.e. less than 1% per year) when used consistently and correctly.  
Acceptable forms of effective contraception are: 
• Combined oestrogen and progestogen containing hormonal contraception (oral, 
intravaginal or transdermal) associated with inhibition of ovulation. 
• Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Male sterilisation (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female patients on the study, the 
vasectomised male partner should be the sole partner for that patient.  
• True abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. 
Periodic 
abstinence 
(e.g. 
calendar, 
ovulation, 
symptothermal, 


 
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post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
• Progesterone-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. The use of 
barrier contraceptives should always be supplemented with the use of a 
spermicide. The following should be noted: 
− Failure rates indicate that, when used alone, the diaphragm and condom are 
not highly effective forms of contraception. Therefore, the use of additional 
spermicides does confer additional theoretical contraceptive protection.  
− However, spermicides alone are inefficient at preventing pregnancy when 
the whole ejaculate is spilled. Therefore, spermicides are not a barrier 
method of contraception and should not be used alone. 
6.2.3.3 Time Period for the Collection of Pregnancy Information 
All pregnancies in female patients receiving at least one dose of Cantrixil will be recorded 
from first dose to 3 months after the final dose. 
6.2.3.4 Follow-up in the Event of a Pregnancy 
If a female patient becomes pregnant, the pregnancy will be recorded and reported to the 
Sponsor within the same timeframe as SAEs (see Section 8.3.2). The Ethics Committee 
and the Sponsor will be informed. The patient will be asked to provide information on the 
outcome of the pregnancy, including premature termination should the case arise.  
Spontaneous miscarriage and congenital abnormalities will be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child 
has been determined on his/her birth. 
6.2.4 Subject Withdrawals 
The Investigator will make every reasonable attempt to ensure that all patients complete 
the study. A patient may withdraw at any time for any reason. The Investigator will 
advise the Sponsor of the withdrawal of any patient. 
A patient may be withdrawn in any of the following circumstances: 
• Adverse event(s), 


 
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• Protocol violation, 
• Recurrence of an unacceptable AE or DLT despite a Cantrixil dose level 
reduction, 
• Withdrawal of consent, 
• Termination of the study by the Investigator or Sponsor,  
• Completion of planned treatment and follow-up period. 
Patients who voluntarily withdraw are termed dropouts. 
Every effort will be made to complete all examinations scheduled on all patients who 
participate in the study, but do not complete the study according to the protocol. The 
Investigator will make every effort to contact patients lost to follow-up. 
Follow-up will continue for any patient with an ongoing AE at the time of study 
completion until the event resolves, or until the Sponsor and the Investigator agree that 
further follow-up is not necessary. 


 
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7 STUDY TREATMENT 
7.1 Investigational Product(s) 
Cantrixil is manufactured as a clear solution for infusion (200 mg). One 10 mL glass vial 
(type I glass, siliconized) with plunger stopper (Westar® Flurotec stoppers) contains 
10 mL of 20 mg/mL of the Active Pharmaceutical Ingredient (API) (TRX-E-002-1) in 
20% Dexolve-7. Before administration, Cantrixil concentrate solution for infusion is 
diluted in sodium chloride 9 mg/mL (0.9%).  
Stability studies are ongoing and the expiration date of the supplied vials may be updated 
during the course of the study as further stability information is available. After dilution, 
Cantrixil for infusion is stable for 24 hours at 2°C to 8°C. To prevent microbial 
contamination, the dilution should be used immediately after preparation. For more 
information on the formulation of Cantrixil, refer to the IB. 
7.1.1 Supply, Packaging and Labelling 
Cantrixil will be supplied to the study centre by Kazia Therapeutics Limited.   
A clinical trial agreement between the study centre and Sponsor will be in place to cover 
all study related activities, prior to receipt of Cantrixil at the study centre. 
7.1.2 Storage and Handling Procedures 
Cantrixil must be stored in the original packaging protected from light in a refrigerator 
(2°C to 8°C). Do not freeze. All Cantrixil will be stored in the storage area of the study 
centre pharmacy, which is a secure, temperature controlled, locked environment with 
restricted access. 
Cantrixil should only be prepared by a pharmacist or healthcare professional trained in 
the handling of cytotoxic drugs.  
7.1.3 Accountability 
In accordance with Good Clinical Practice, the study centre will account for all supplies 
of Cantrixil. Details of receipt, storage, assembly and return will be recorded.  
All unused supplies of Cantrixil will either be destroyed by the study centre or returned to 
the study Sponsor at the end of the study in accordance with instruction by the Sponsor. If 
the Sponsor authorises destruction at the study centre, the Investigator must ensure that 
the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided. Certificates of destruction must 
be completed and sent to the Sponsor. 


 
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7.2 Dosage and Administration 
Dilution Instructions 
Cantrixil should be prepared by a pharmacist or healthcare professional trained in the 
handling of cytotoxic drugs and aseptic technique must be used; ideally an aseptic suite 
will be used to prepare Cantrixil for administration. The outer surface of the vial is not 
sterile. 
• Based on the dose, the appropriate amount of air is extracted into an appropriately 
sized syringe and needle. 
• An additional air buffer should be included in the syringe. 
• The plastic lid from the Cantrixil pre-filled vial is removed. 
• The syringe needle is inserted through the rubber stopper of the vial being careful 
not to core the rubber stopper. 
• The appropriate volume of the vial (Cantrixil concentrate plus air buffer) is 
extracted from the vial into the syringe; this process may need to be repeated if 
multiple vials are required to achieve the necessary volume of drug. 
• The syringe and needle is shaken gently to eliminate any air bubble(s) from the 
syringe. 
• Eject the entire contents of the syringe into a sterile bag of saline for infusion to 
result in a total volume of 100 mL of fluid for infusion. Note that if a patient 
weighs more than 100kg then more than 100mL of undiluted Cantrixil would be 
required to dose at 20mg/kg. Please contact the IQVIA CRA for instructions 
under these circumstances.  
• The plunger rod MUST NOT be drawn back to rinse the syringe, in order to avoid 
contamination and to ensure that the correct volume is ejected. 
• The peelable sticker, which is provided on the inner side of the Cantrixil carton 
box, displaying the text “Intraperitoneal use only.” must be attached to the saline 
infusion pack containing the diluted Cantrixil solution for intraperitoneal infusion. 
This is a precautionary measure to ensure that Cantrixil is infused only via the 
intraperitoneal route of administration.  
Method of administration 
Cantrixil must be administered via the intraperitoneal route only; an in-line filter must be 
part of the infusion set. The Cantrixil solution should be warmed before administration. 
Once warm, the infusion bag should be hung and the drug allowed to infuse under gravity 
flow. Subsequent to each Cantrixil administration up to 1 L of warmed sodium chloride, 


 
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9 mg/mL (0.9%) solution for injection shall be infused to support distribution of the 
Cantrixil solution in the abdominal cavity. 
Delivery of Cantrixil and combination chemotherapy 
All patients will have catheters/ports inserted to facilitate intraperitoneal chemotherapy 
administration. This intervention should be scheduled to occur as soon as possible after 
enrolment. All ports/catheters will be inserted by an interventional radiologist or surgeon 
and checked for patency and leakage. Patients will be referred to the interventional 
radiologist or surgeon by their treating oncologist. For intraperitoneal ports, the minimum 
period between port placement and the first administration of Cantrixil must not be 
shorter than 7 days. For other intraperitoneal access devices, the period may be shorter if 
adequate stability and/or healing of the delivery system’s insertion site is confirmed by 
the treating physician. 
Insertion of the intraperitoneal port/catheter and intraperitoneal administration of 
Cantrixil and standard chemotherapy will be done in accordance to each study centre’s 
Standard Operating Procedures and guidelines, or the recommended guidelines listed in 
Appendix B. 
The exact time that the intraperitoneal infusion has completed must be recorded. 
Cycles 3 to 8 of Parts A and B of the study will include Cantrixil in combination with a 
standard chemotherapy agent selected for the patient from Table 1 by the treating 
physician/ Investigator. Standard therapies will be administered according to the 
schedules listed in Table 1 and recorded appropriately in the patient medical record and 
study eCRFs. Before administration of the combination chemotherapy, the PK results for 
each patient from Part A/ Cycle 1 will be reviewed by the DSMC to ensure that the PK 
profile of Cantrixil is indeed compatible with the proposed schedule for the combination 
chemotherapy agent. 
With the anticipated PK profile of Cantrixil, combination chemotherapy agents should not 
be administered within 24 hours of Cantrixil dosing to avoid any adverse drug-drug 
interactions. 
Cycles of Cantrixil and the combined chemotherapy may continue until the patient fulfils 
any of the off-therapy criteria, as described in Section 6.1. It is recommended that the 
catheter/port remains in the abdominal cavity during the entire treatment period. If a 
catheter is used it is to be kept closed between infusions. 
7.3 Treatment Strategy 
The clinical staff at the study centre are all responsible for the ongoing safety and 
well-being of the subjects while they are in the study centre.  


 
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As this is the first time that Cantrixil is being administered to patients, the study centre 
should be equipped with the necessary facilities to enable staff to manage potentially 
life-threatening events. There should be a paging system to alert the clinical staff to any 
area in the study centre where a patient may need medical attention. In the case of an 
emergency, cardiac resuscitation trolleys are to be found in the main ward areas of the 
study centre. These trolleys contain drugs, equipment for airway insertion, circulation 
lines, defibrillation etc., together with oxygen cylinders and portable suction machines. 
There is to be a physician on site 24 hours a day. In addition, if necessary the clinical staff 
can contact further on-call physicians or public emergencies services, including the 
ambulance and hospital resuscitation team, in the event of a serious medical event. 
Equipment and emergency drugs are to be available to treat common medical 
emergencies that might occur in a Phase I study at the study centre.  
7.4 Warnings and Precautions 
As this is the first administration of Cantrixil to humans, all effects cannot be reliably 
predicted. The pre-clinical data suggest an acceptable safety margin. Facilities and staff 
for resuscitation and the treatment of other medical emergencies must be provided. 
7.5 Prior and Concomitant Medication 
In the interests of patient safety and acceptable standards of medical care the Investigator 
will be permitted to prescribe supportive care treatment(s) at his/her discretion. Palliative 
radiotherapy is permitted on this study but not within the peritoneum and also not during 
MTD cycle (Cycle 1). All treatments must be recorded in the patients’ eCRF (medication, 
dose, treatment duration and indication).  
As TRX-E-002-1, the active ingredient of Cantrixil, may inhibit CYP450 drug 
metabolising enzymes, including CYP2C9, CYP2C8, CYP2C19, CYP2B6, CYP3A4, 
CYP2D6, CYP2A6 and CYP1A2, caution should be taken when administering drugs that 
are metabolised by CYP450 enzymes until further information is available. In particular, 
the potential interaction between TRX-E-002-1 and paclitaxel, a CYP2C9 substrate 
frequently used in the treatment of ovarian cancer, needs to be considered. As such the 
use of paclitaxel is allowed, but only 24 hours after Cantrixil administration. 
 
7.6 Method of Assigning Subjects to Treatment Groups 
At screening, potential study patients will be assigned a screening number. The screening 
number will be prefixed with SCR. Following confirmation of eligibility, at study 
treatment administration, patients will be assigned a patient number in the order in which 
they are enrolled in the study.  


 
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If applicable, replacement patients will receive the same treatment allocation as those 
whom they replace. 
Patients who are replaced will be allocated the same treatment number prefixed with the 
number 1 e.g. if treatment number 009 is replaced then the replacement number will 
be 109. 
7.7 Randomisation Procedures (Not applicable) 
7.8 Maintenance of Randomisation Codes (Not applicable) 
7.9 Blinding (Not applicable) 


 
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8 STUDY PROCEDURES 
Study assessments and procedures to be performed during the study are detailed in the 
Schedule of Assessments, Section 16; Table 4. All visits during treatment cycles 1 to 8 
have a window of +/- 1 calendar day. During follow-up, the window is extended to +/- 1 
week. The screening period is up to 28 days before the Cycle 1 Day 1 dose of Cantrixil. 
8.1 Pharmacokinetic Assessments  
Plasma Samples 
Pharmacokinetic studies will be performed on all patients. At each of the sampling 
periods a blood sample will be collected into a 4mL dipotassium EDTA tube and the 
sample processed to plasma. The plasma samples will be divided into a primary and 
back-up sample and stored frozen at -80°C. The primary sample will subsequently be 
shipped to the bioanalytical laboratory. The results of the PK analysis will not be made 
available to the Principal Investigator, Investigators or any study centre staff during the 
study. The results will be made available to the DSMC/B for the purposes of patient 
safety. Blood sample collection times are included in the Schedule of Assessments (see 
Section 16). 
Bioanalysis 
All bioanalytical procedures will be performed by TetraQ (The University of Queensland, 
Brisbane, Queensland, Australia), according to their internal quality assurance protocols 
and procedures. Concentrations of TRX-E-002-1 in plasma will be determined using a 
validated liquid chromatography tandem mass spectrometry (LC-MS/MS) based assay. If 
one or more of the major active metabolites of TRX-E-002-1 is known to contribute at 
least 10% of the activity or toxicity observed, the PK of that/those metabolite(s) will also 
be measured. Full details of the bioanalytical analysis will be included separately in the 
Bioanalytical Report. 
8.2 Efficacy Assessments  
The following efficacy assessments will be measured (sample collection times are 
included in the Schedule of Assessments [see Section 16]): 
• PFS will be measured as the time from treatment starts until objective tumour 
progression as defined by RECIST version 1.1 criteria or GCIG criteria (see 
Appendix C).  
• The time to paracentesis will be measured as the time from treatment begin until 
the next paracentesis event.  


 
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• The volume of paracentesis will be measured by estimating the volume of 
malignant ascites drained at each event. 
• Disease response will be measured using RECIST version 1.1 criteria; the 
Gynecological Cancer Intergroup (GCIG) response criteria (described in Rustin et 
al., 2011), which incorporates RECIST 1.1 and CA-125 measurements, may also 
be used to define disease response during Follow-up. Although the GCIG 
response criteria incorporating CA-125 measurements has been used successfully 
in clinical trials for recurrent ovarian cancer (Alexandre et al., 2012), patients are 
not evaluable for CA-125 if there has been a surgical or medical interference with 
their peritoneum during the past 28 days. Only the baseline and Follow-up 
measurements of CA-125, therefore, may be reliably used for determining 
response and progression in this study. During Follow-up, the GCIG criteria, 
summarised in Appendix C, may be used to define response and progression.  
• Concentration of CA-125 in peripheral blood will be assayed in local hospital 
laboratories at baseline using locally validated assays at baseline and then weekly 
during treatment, at the End of Treatment and during Follow-up. These 
measurements may not be used to determine progression or disease response until 
28 days after the last IP chemotherapy administration.  
The following exploratory endpoints will also be assessed: 
• Enumeration of CETC in peripheral blood and malignant ascites (if present) will 
be assayed using the MAINTRAC® CETC Count method by Genostics or similar 
methodology. This method uses a fluorochrome-labelled antibody against surface-
epithelial antigen (EpCam) to tag CETCs. Image analysis allows CETC numbers 
to be calculated in relation to blood volume over the course of treatment. Samples 
will be assayed at baseline, at the end of Cycle 2 and at the End of Therapy for 
patients in Part A of the study only.  
• Clonogenicity of CETCs in peripheral blood and malignant ascites (if present) 
will be measured using the MAINTRAC® Tumour Sphere Units assay by 
Genostics or similar methodology. Samples will be assayed at baseline, at the end 
of Cycle 2 and at the End of Therapy for patients in Part A of the study only. 
• Expression of stem cell markers in the isolated colonies will be measured using 
labelled antibodies and scanning fluorescent microscopy techniques by Genostics 
or similar facility. 
• Efficacy of twice weekly doses of Cantrixil as a monotherapy and combination 
therapy. 


 
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These exploratory endpoints, if assessed, will be reported separately from the Clinical 
Study Report. 
8.3 Safety Assessments  
8.3.1 Adverse Events 
Definitions: 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be any clinically significant sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Patients will be followed for 3 months after discontinuing therapy or until death, 
whichever occurs first. Patients removed from study for unacceptable AEs will be 
followed until resolution or stabilisation of the AE. 
Note that for this study, disease progression will not be defined as an adverse event. 
Disease progression will be recorded as a participant outcome but not recorded on the 
adverse event log.  
Adverse Drug Reaction (ADR) 
Any untoward and unintended response in a patient to an investigational medicinal 
product which is related to any dose administered to that patient. 
Serious Adverse Event (SAE) 
An adverse reaction is ‘serious’ if it: 
• Results in death; 
• Is life-threatening; 
• Requires hospitalisation or prolongation of existing hospitalisation, excluding 
hospitalisation for planned therapy or convenience of the participant; 
• Results in persistent or significant disability or incapacity; 
• Consists of a congenital anomaly or birth defect; 
• Is a medically important event. 


 
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Unexpected Adverse Reactions 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the medicinal product in question set out: 
• In the case of a product with a marketing authorisation, in the summary of product 
characteristics for that product; 
• In the case of any other investigational medicinal product, in the IB relating to the 
trial in question. 
8.3.2 Reporting of Adverse Events 
All adverse events must be fully recorded in the patient’s eCRF from signing of informed 
consent until 30 days after the last dose of Cantrixil, whether or not they are considered to 
be drug-related. Adverse events that occur within the second and third month of the 
follow-up period should only be recorded if the investigator deems them to be related to 
the investigational agent. Signs and symptoms of each AE should be described in detail: 
onset time and date, offset time and date, description of event, severity, relationship to 
investigational product, action taken and outcome. The descriptions and grading scales 
found in the revised NCI-CTCAE version 4.03 will be utilised for AE reporting. 
Adverse events should be followed until recovery to the normal state has been achieved. 
In the event of a patient not returning to the study centre, the outcome of this event will 
be recorded as lost at follow-up. 
Reporting of SAEs and SUSARs 
SAEs occurring from the time of informed consent will be reported to the Sponsor’s 
medical representative within 24 hours of the Investigator becoming aware of the event. 
The Investigator will be requested to complete a separate SAE reporting form in addition 
to the information in the eCRF. 
A suspected unexpected serious adverse reaction (SUSAR) which is fatal or 
life-threatening must be reported to the competent authority and Ethics Committee 
immediately (within 7 days or according to local reporting requirements)) after the 
Sponsor became aware of the event. Any additional information must be reported within 
eight days of sending the first report.  
A SUSAR which is not fatal or life-threatening must be reported to the competent 
authority and Ethics Committee as soon as possible (within 15 days or according to local 
reporting requirements) after the Sponsor becomes aware of the event. 
8.3.3 Categorisation of Adverse Events 
Adverse events will be graded according to the NCI-CTCAE version 4.03. Events which 
do not fit into any CTCAE category will be categorised as follows: 


 
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1 
Mild: 
Mild events are those which are easily tolerated with 
no disruption of normal daily activity. 
2 
Moderate: 
Moderate events are those which cause sufficient 
discomfort to interfere with daily activity. 
3 
Severe: 
Severe events are those which incapacitate and 
prevent usual activity. 
4 
Life-threatening: 
Life-threatening events have extremely serious 
consequences and urgent intervention is indicated to 
avoid a fatal outcome. 
5 
Death: 
Death related to an AE 
8.3.4 Causal Relationship Assessment 
The Principal Investigator will assess causal relationship between the study treatment and 
each AE, and answer ‘yes’ or ‘no’ to the question: ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the study treatment?’. For 
SAEs causal relationship will also be assessed for study treatment, other medication and 
study procedures. 
8.3.5 Action Taken 
Action taken will be defined as: 
• None; 
• Dosing interrupted; 
• Dosing stopped; 
• Infusion delay. 
8.3.6 Outcome 
Outcome will be defined as: 
• Not recovered/not resolved; 
• Recovered/resolved; 
• Recovered/resolved with sequelae; 
• Fatal; 
• Unknown/lost to follow-up. 


 
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8.3.7 Coding of Adverse Events 
All AEs will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). Adverse events will be categorised for severity according to the 
NCI-CTCAE Version 4.03. 
8.3.8 Pregnancy Reporting 
All pregnancies should be reported by the Investigator within 24 hours of notification on 
a Pregnancy Report Form.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and 
documented accordingly on the Pregnancy Report Form. 
Although pregnancy itself is not regarded as an AE, congenital abnormalities/birth defects 
and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions 
without complications should not be handled as AEs. 
8.4 Clinical Laboratory Safety Tests 
Sample collection times are included in the Schedule of Assessments (see Section 16). 
Clinical laboratory tests include haematology, serum chemistry and urinalysis and are 
listed below. 
Panel 
Parameter 
Haematology 
White blood cell count 
Neutrophils absolute 
 
Red blood cell count 
Lymphocyctes absolute 
 
Haemoglobin  
Monocytes absolute 
 
Haematocrit  
Eosinophils absolute 
 
Mean corpuscular volume  
Basophils absolute 
 
Mean corpuscular haemoglobin  
Platelets 
 
Mean corpuscular haemoglobin concentration  
 
Serum  
Alkaline phosphatase  
Sodium 
biochemistry 
Alanine aminotransferase  
Potassium 
 
Creatine kinase  
Urea 
 
Gamma glutamyl transpeptidase  
Creatinine 
 
Lactate dehydrogenase  
Albumin 
 
Aspartate aminotransferase  
Calcium 
 
Total Bilirubin 
Phosphate 
 
Globulin 
Glucose 
 
Chloride 
Magnesium 
Coagulation 
Activated partial thromboplastin time  
International normalised ratio 
Urinalysis 
Leucocytes 
Red blood cells 
(Dip-stick) 
Protein 
pH 
 
Bilirubin 
Nitrite 
 
Urobilinogen 
Specific gravity 
 
Ketones 
Glucose 
 
Microscopy (if clinically indicated) 
 
Pregnancy test 
(serum) 
Beta human chorionic gonadotropin 
 
 


 
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Additional and repeat testing may be performed at the discretion of the Investigator. 
Unless otherwise specified in the Laboratory Manual all clinical laboratory tests will be 
performed by an accredited local laboratory near or at the study centre.   
8.5 Clinical Safety Assessments 
Assessment times are included in the Schedule of Assessments (see Section 16). 
8.5.1 Physical Examination 
Physical examinations will be performed by a physician and will include the examination 
of the following: general appearance, head, eyes, ears, nose, throat, chest/ respiratory, 
heart/ cardiovascular, gastrointestinal/ liver, musculoskeletal/ extremities, dermatological/ 
skin, thyroid/ neck, lymph nodes, neurological/ psychiatric. Complete physical 
examinations will be performed at screening and the final study visit. Symptom-driven 
physical examinations will be performed where indicated at other specified time points, 
per the Schedule of Assessments (Table 4). 
8.5.2 Vital Signs 
Systolic and diastolic blood pressure (SBP, DBP), pulse rate, respiratory rate and body 
temperature will be recorded as specified in the Schedule of Assessments (Table 4) after 
the subject has been in a supine position for at least 5 minutes. Blood pressure, pulse rate, 
and respiratory rate should be obtained at a comfortable room temperature, with the 
subject’s arm unconstrained by clothing or other material. All measurements will be 
obtained from the same arm and, using an automatic instrument with a digital readout, 
throughout the study. All readings must be recorded in the eCRF. Additional readings 
may be taken at the discretion of the Investigator. 
8.5.3 12-Lead Electrocardiogram (ECG) 
Computerised 12-lead ECG recordings will be obtained according to the Schedule of 
Assessments (Table 4). Each lead shall be recorded for at least 3 beats at a paper speed of 
25 mm/sec. Subjects will rest in a supine position for at least 5 minutes prior to 
recordings. Recordings will be obtained in triplicate. 
The following parameters will be recorded: rhythm, ventricular rate, PR interval, QRS 
duration and QT. The RR value will also be recorded so that the QTcF values can be 
calculated automatically by formula.  
Where the ECG is recorded as abnormal, the abnormality will be specified. 
8.5.4 Medical History 
A complete medical history will include evaluation (past or present) of the following:  
general, head and neck, eyes, ears, nose throat, chest/ respiratory, heart/ cardiovascular, 
gastrointestinal/ liver, gynaecological/ urogenital, musculoskeletal/ extremities, skin, 


 
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neurological/ psychiatric, endocrine/ metabolic, hematologic/ lymphatic, allergies/ drug 
sensitivities, past surgeries and clinical outcomes, substance abuse or any other diseases 
or disorders. All prior cancer treatments and the clinical outcomes will also be recorded. 
8.6 Follow-up Assessments 
Patients will be followed for 3 months after discontinuing therapy or until death or 
consent withdrawal, whichever occurs first (see Schedule of Assessments in Follow-up, 
Table 6). Patients withdrawing consent for the study, who have study-related AEs, are 
encouraged to continue visits until resolution or stabilisation of the AEs. Patients that are 
beginning on another treatment therapy before the end of the follow-up period must be 
formally withdrawn from this study. In this case, safety data should be collected until the 
day before the first study intervention on the new study. 


 
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9  DATA COLLECTION 
A 21 CFR part 11 compliant Electronic Data Capture (EDC) system will be used for this 
study. Electronic CRFs will be utilised. An eCRF is required to be completed for each 
subject who provides informed consent. The completed eCRFs are the sole property of 
the Sponsor and should not be made available in any form to third parties, except for 
authorized representatives of the Sponsor or appropriate regulatory authorities, without 
written permission from the Sponsor. The Investigator has ultimate responsibility for the 
collection and reporting of all clinical, safety and laboratory data entered on the eCRFs 
and any other data collection forms (source documents) and ensuring that they are 
accurate, 
authentic/original, 
attributable, 
complete, 
consistent, 
legible, 
timely 
(contemporaneous), enduring and available when required. Any corrections to entries 
made in the source documents must be dated, initialled and explained (if necessary) and 
should not obscure the original entry. 
In most cases, the source documents are the study centre or the physician's subject chart 
or patient medical record. In these cases, data collected on the eCRFs must match the data 
in those charts or medical records. All source documents will be retained by the study 
centre.  
In some cases, the eCRF, or part of the eCRF, may also serve as source documents. In 
these cases, a document should be available at the study centre as well as at the Sponsor 
clearly identifying those data that will be recorded in the eCRF, and for which the eCRF 
will stand as the source document 
Photocopies of completed source documents will be provided only if essential (i.e. for 
regulatory purposes) at the request of the Sponsor. 
The informed consent will be kept at the study centre with a copy of the completed source 
documents in the appropriate Investigator site file folder provided, or a note to indicate 
where the records can be located. All records should be kept in conformance to applicable 
national laws and regulations. 
Validity and consistency of data will be checked by employing pre-programmed data 
validation rules that will be applied to the data extracted from the EDC system during the 
course of the study. The data management team will raise queries in the EDC system to 
resolve discrepancies. The Investigator must verify that all data entries in the eCRFs are 
accurate and correct. After completion of the study and when all collected data is 
validated, the database will be locked, pursuant to the prior approval by the Sponsor. 
Final data will be extracted from the EDC and delivered to the Sponsor in the form of 
SAS® datasets. A PDF copy of the eCRF will be produced for each study subject and 
included in the final delivery. 


 
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All eCRF entries, corrections, and alterations must be made by the Investigator or other, 
authorised, study centre personnel and only by individuals who have received training on 
the EDC system. Study centre personnel may be allowed access to the system only after 
training is completed. Training must be documented and a log of all EDC users and their 
rights within the system be maintained. 
Adverse events will be coded using the current MedDRA thesaurus; concomitant 
medication will be coded using the World Health Organisation (WHO) Drug Dictionary 
(DD) (if required). 
The EDC system will keep track of all data entries, alterations and query resolution in an 
audit trail. The audit trail will form an integral part of the database and will be archived 
alongside the data. 


 
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10  EVALUATION OF STUDY DATA 
10.1  Evaluation of Pharmacokinetic Parameters 
Summary statistics will be presented for Cantrixil (TRX-E-002-1) plasma concentrations 
at each scheduled time point by dose cohort (for example, mean, geometric mean, 
median, standard deviation [SD], standard error of the mean [SEM], coefficient of 
variation [CV] and range). Summary statistics will also be presented by dose cohort for 
all Cantrixil PK parameters, including  
• Area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration (AUC0-last), 
• Maximum plasma concentration (Cmax) and 
• Time to maximum plasma concentration (tmax), plus if estimable:  
• Area under the plasma concentration-time curve from time zero extrapolated to 
infinity (AUC0-∞), 
• Apparent terminal half-life (t1/2), 
• Clearance (CL) and  
• Volume of distribution (Vd).  
All concentrations below the limit of quantification and/or missing data will be labelled 
as such in the concentration data listings. Concentrations below the limit of quantification 
which are after Cmax will be treated as missing in summary statistics and for the 
calculation of pharmacokinetic parameters. Pharmacokinetic parameters will be 
determined by standard non-compartmental pharmacokinetic analyses using Phoenix 64 
WinNonLin software. 
The PK assessment results will be described in a PK study report prepared by TetraQ at 
completion of the study. 
10.2  Evaluation of Pharmacodynamic/Efficacy Measures 
Not applicable. 
10.3  Evaluation of Safety 
The safety evaluation will include vital signs, ECG parameters, clinical laboratory tests 
(haematology, serum biochemistry, coagulation, urinalysis and urine microscopy [if 
clinically indicated]) and AEs. 


 
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11  STATISTICAL METHODS  
The default summary statistics for continuous variables include number of contributing 
observations (n), mean, SD, median, minimum and maximum.   
For categorical variables, the number (n) and percentage (%) (the percentage of subjects 
in each category relative to the total number of subjects in the relevant analysis 
population or relative to the total number of subjects in the relevant analysis population, 
with assessments available [where appropriate]) in each category will be the default 
summary presentation.  
Unless otherwise specified, “Baseline” is defined as the last observed value of the 
parameter of interest prior to the first intake of study medication (this includes 
unscheduled visits). For numerical variables, change from Baseline will be calculated as 
the difference between the value of interest and the corresponding baseline value. 
Unless otherwise specified, all statistical estimates will be provided at the 5% 
significance level. In case of normality assumption violation, an appropriate 
non-parametric method will be used for analysis, where applicable. 
All data will be presented in by-subject listings. 
The statistical analysis will be performed using SAS® Version 9.2 or higher. 
All details regarding the statistical analysis and the preparation of tables, listings and 
figures will be described in the Statistical Analysis Plan (SAP) prepared by IQVIA and 
approved by the Sponsor before database lock. 
11.1  Sample Size Determination 
For this Phase I dose-escalation study to determine the MTD of Cantrixil as a 
monotherapy and to investigate the safety and tolerability as combined with standard 
chemotherapy, an appropriate sample size is not statistically determined.  
The dose-escalation Cycle 1/Part A of the study is designed to determine the MTD of 
Cantrixil as a monotherapy in patients with ovarian cancer, Fallopian tube cancer or 
primary peritoneal cancer. The planned dose levels include 0.24, 0.6, 1.25, 2.5, 5, 10 and, 
20 mg/kg. From initial dose level, single patient cohorts will be used until an AE is 
observed during Part A/Cycle 1 that meets the definition of a DLT or warrants further 
examination in the opinion of the Principal Investigator and the DSMC/B (see Section 
6.1) and then the dose escalation will follow the 3+3 dose escalation model to treat up to 
3 to 6 patients at each escalating dose level. After Cycle 2, which is another cycle of 
Cantrixil monotherapy, patients will continue at the same dose level combined with 
standard chemotherapy through Cycles 3 to 8 in Part A of the study. Patients who don’t 
experience a DLT but who do not complete Cycle 1 of therapy will be replaced. To 


 
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establish MTD in Part A/Cycle 1 of the study, up to 42 patients will be enrolled. An 
expanded cohort with 12 patients will be enrolled and treated at MTD in Part B of the 
study.  
The total sample size may be up to 54 patients (up to 42 in Part A, 12 in Part B) enrolled 
into this study.   
11.2  Subject Populations for Analyses 
Maximum Tolerated Dose (MTD) population:  
The MTD population will include all patients who experienced DLTs in Cycle 1/Part A, 
and those who received all three weekly doses of study treatment in Cycle 1/Part A. The 
safety data regarding the Cycle 1/Part A will be used to determine MTD from this 
analysis population. 
Safety (SAF) population:  
The SAF population will include all enrolled patients who receive at least 1 dose of study 
treatment. All safety analyses will be conducted on this population.  
Pharmacokinetic (PK) population:  
The PK population will include all SAF patients who with at least 1 PK assessment. All 
PK analyses will be conducted on this population.   
Intent-to-Treat (ITT) population:  
The ITT population will include all enrolled patients who receive at least 1 dose of study 
treatment and from whom at least 1 post-baseline efficacy measurement is obtained. All 
efficacy analyses will be conducted on this population and will be based on the actual 
dose level/single-weekly or twice weekly doses of Cantrixil at which each patient has 
been treated. 
The number and percentage of the patients included in the analysis populations will be 
reported in a table showing the reason of exclusion for all patients enrolled into study. A 
listing of reasons of exclusion from analysis population will be provided. Patients who 
were screened but never started a dose will be listed. Screening failures will not be 
included in any of the summary tables. 
11.3  Pharmacokinetic Analysis 
Summary statistics will also be presented by dose cohort for all Cantrixil PK parameters 
described in Section 10.1.  
The PK assessment results will be described in a PK study report prepared by TetraQ at 
completion of the study. 


 
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11.4  Efficacy Analysis 
Disease response will be measured using RECIST version 1.1 criteria; disease response 
may also be assessed using the Gynecological Cancer Intergroup (GCIG) response 
criteria that incorporates CA-125 measurements during Follow-up (see Appendix C). 
Assessment of target lesions response (Complete Response; Partial Response; Progressive 
Disease; Stable Disease), non-target lesions response (Complete Response; Stable 
Disease; Partial Response) and CA-125 expression changes will be summarised using 
frequency and percentage of patients in each response category by dose cohort. 
Responses will be reported separately for both RECIST 1.1 and CA-125 criteria.  
The Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be 
provided along with their 2-sided 95% confidence intervals (CIs) for PFS.  
The time to paracentesis data will also be summarised as another time-to-event endpoint. 
The volume of abdominal fluid will be summarised using descriptive statistics by dose 
cohort. 
11.5  Exploratory Analysis 
Enumeration and Clonogenicity of CETC in peripheral blood and malignant ascites will 
be performed at baseline, at the end of Cycle 2 and at the End of Therapy. Continuous 
response data (CETC numeration) will be summarised for each dose cohort. For 
continuous data like CETCs, number of colonies and number of colonies positive per mL 
of blood and/or per CETC for a stem cell marker, descriptive statistics will be provided.  
More details on analysis method or data presentation will be described in the SAP.  
11.6  Safety Data Analysis 
Demographic and baseline disease characteristics data including age, gender, height, 
weight, tumour type, medical condition, etc. will be listed individually by patient and 
summarised descriptively by dose cohort using descriptive statistics (number of 
observations, median, minimum, maximum, mean and SD). Categorical variables 
(gender, ethnicity and race) will be summarised using frequencies and percentage. The 
SAF population will be used. 
Maximum tolerated dose 
For determination of the MTD, individual subject data from the dose escalation part 
(Cycle 1/Part A) will be reported. In addition, for the final statistical analysis, the 
following will be analysed: 
• At each dose level, the number and proportion of subjects in the DLT population 
who experience a DLT during the first DLT evaluation period (Cycle 1/Part A). 


 
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• At each dose level, the number and proportion of treatment emergent AEs 
(TEAEs) experienced by subjects in the DLT population during the first DLT 
evaluation period (Cycle 1/Part A). 
The MTD will be determined according to the dose-escalation plan described in 
Section 6.1.2 (Table 3).  
The MTD is defined as the highest dose level at which no more than 1 subject out of 
6 subjects treated in a cohort and evaluable for DLT determination experiences a DLT. 
Safety and tolerability 
Safety analyses will be performed on the SAF population. 
Adverse events will be coded using MedDRA and will be summarised by System Organ 
Class (SOC), Preferred Term, and dose cohort. Severity of AEs will be graded using the 
CTCAE version 4.03 toxicity grading scale. Adverse events will be further summarised 
by maximum severity and relationship to study treatment. Prior and concomitant 
medications will be summarised by dose cohort. Standard chemotherapy medications will 
be separately summarised by dose cohort. Safety laboratory tests and vital signs 
assessments, will be summarised by dose cohort using statistics for continuous or 
categorical data, as appropriate.   
Dose limiting toxicities, safety and tolerability data will also be separately summarised 
for Cycles 1 and 2, and Cycles 3 to 8 at MTD from Part A and Part B study, as 
appropriate. A detailed SAP will be finalised prior to clinical database lock of the study. 
Concomitant Medications 
All medications will be coded using the WHO-DD and Anatomical Therapeutic Chemical 
(ATC) system. Each medication will be classified as prior medication if it is stopped prior 
to the first dose of Cantrixil, or as concomitant medication if it is on-going at the time of 
the first dose or is started after the first dose of Cantrixil. Prior and concomitant 
medications will be summarised by dose cohort by ATC level 2 categories and preferred 
name. 
Standard chemotherapy medications and regimen of patients will be summarised and 
listed separately. 
Laboratory abnormalities 
All laboratory values will be converted into SI units, as appropriate, and the severity 
grade calculated using CTCAE, version 4.03. Parameters for which a grading does not 
exist will be classified into low/normal/high group by means of laboratory normal ranges. 
For each laboratory test (e.g. haematology, biochemistry) a listing of laboratory values 
will be provided by laboratory parameter, patient and dose cohort. The frequency of 


 
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notable lab abnormalities (i.e. newly occurring CTCAE Grade 3 or Grade 4 laboratory 
toxicities), will be displayed by parameter, cycle, and dose cohort. A separate listing will 
display notable laboratory abnormalities (i.e., newly occurring CTCAE Grade 3 or 
Grade 4 laboratory toxicities).  
Laboratory data will be summarised by presenting grade shift tables for those parameters 
for which CTCAE version 4.03 allows classification. All remaining data will be 
summarised by presenting shift tables based on normal ranges. Laboratory data will also 
be displayed by presenting descriptive statistics of raw data and change from baseline 
values (means, medians, standard deviations, ranges). 
Vital Signs 
Vital signs results will be presented using descriptive statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges). 
Physical Examinations 
Physical examination results will be summarised using frequency tables for 
normal/abnormal results per visits.  


 
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12  STUDY REPORT  
A clinical study report, compliant with the requirements of ICH E3, will be prepared by 
IQVIA.  


 
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13  REGULATORY AND ETHICAL ISSUES 
13.1  Regulatory and Ethics Review and Approval 
This study is to be conducted according to globally accepted standards of GCP (as 
defined in the ICH E6 Guideline for GCP), in agreement with the latest revision of the 
Declaration of Helsinki and in keeping with local regulations. Before initiation of the 
study, approvals from the applicable Regulatory Authority(ies) will be obtained where 
relevant. The Investigator must obtain approval or favourable opinion of the protocol, 
Informed Consent Form (ICF) and any advertisement for patient recruitment from the 
Ethics Committee complying with the applicable pertinent government regulations. The 
Ethics Committee will evaluate the ethical, scientific and medical appropriateness of the 
study. 
The documents submitted will include but are not limited to; 
• The final protocol, 
• The IB, 
• The ethics application form, 
• The ICF. 
The study will not commence unless the following conditions are satisfied: 
• The IRB has given a favourable opinion in relation to the study; and 
• The study has been authorised by the licensing authority. 
13.2  Informed Consent 
Before any study-related activities are carried out such as Screening and enrolment, each 
prospective candidate will be given a full explanation of the study, allowed to read the 
approved ICF in a local language and will be provided ample time and opportunity to ask 
any questions that may arise. Once all questions have been answered and the Investigator 
is assured that the individual understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing and 
personally dating the ICF. The Investigator will provide a copy of the signed and dated 
ICF to each patient.  
The nature of the ICF will comply with the current version of the Declaration of Helsinki, 
the current requirements of GCP and local regulations, which ever provides the greater 
patient protection.  
If an amendment to the Clinical Study Protocol (CSP) changes the patient participation 
schedule in scope or activity, or increases the potential risk to the patient, the ICF must be 


 
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revised and submitted to IRB for review and approval or favourable opinion. The revised 
ICF must be used to obtain consent from any patient currently enrolled in the study if 
he/she is affected by the amendment. The revised ICF must be used to obtain consent 
from any new patients who are enrolled into the study after the date of the approval or 
favourable opinion of the amendment by IRB. 
The signed and dated declaration of informed consent will remain at the Investigator’s 
study centre, and must be safely archived by the Investigator so that the ICFs can be 
retrieved at any time for monitoring, auditing, and inspection purposes.  
13.3  Indemnity and Compensation 
The Sponsor will indemnify the Investigators from all and any claims arising out of this 
study except for their negligence or malpractice and providing that the study is conducted 
according to the standards established by the protocol. 
In the event that it can be demonstrated that a patient suffers any significant deterioration 
in health or well-being or any harmful susceptibility or toxicity as a direct result of their 
participation in this study then the Sponsor will agree to abide by the current Food and 
Drug Administration Guidelines, as well as any local regulations that may apply, with 
regard to compensation payable to the patient. The amount of compensation will be 
calculated by reference to the level of damages commonly awarded in law for similar 
injuries at the time when such an injury occurred. 
The Investigators declare to having insurance cover for the malpractice and/or negligence 
of their employees and agents. 
 
 


 
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14  STUDY MANAGEMENT  
14.1  Quality Assurance and Quality Control 
In accordance with the guideline for ICH GCP, the Sponsor has responsibility for 
implementing and maintaining quality assurance and quality control systems, and the 
ultimate responsibility for the quality integrity of the trial data resides with the Sponsor. 
Data will be captured in a standardised format according to the study centre’s standard 
operating procedures and those procedures specified in the study documentation. 
A 21 CFR part 11-compliant EDC system will be used for this study. The eCRFs will be 
produced for each patient.  
The Investigator will ensure the accuracy, completeness and timeliness of the data 
recorded for data queries and all required reports according to any instructions provided. 
14.2  Protocol Adherence 
The protocol must be read thoroughly and the instructions followed exactly. Any 
deviations should be agreed by both the Sponsor and the Investigator, with the 
appropriate written and approved protocol amendments made to reflect the changes 
agreed upon. Where the deviation occurs for the well-being of the patient, the Sponsor 
must be informed of the action agreed upon. No prospective protocol waivers will be 
granted by the Sponsor. 
14.3  Documents Necessary for Initiation of Study 
The following documents will be available prior to the first administration of the study 
treatment to the first patient: 
• Regulatory authorisation; 
• Copy of current Investigator’s Brochure; 
• Risk assessment report; 
• Completed and signed Investigator agreement/contract; 
• Signed original of the final protocol; 
• Ethics Committee approval; 
• Copy of the constitution of the Research Ethics Committee;   
• A list of members of the Ethics Committee; 
• A copy of the consent form and patient information to be used; 
• The curriculum vitae of all Investigators; 


 
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• A clinical trial agreement between the Sponsor and the study centre defining the 
responsibilities of the Sponsor, the study centre and any third parties significantly 
involved in the supply chain of the IMP, where applicable; 
• A list of laboratory reference range values for parameters measured in the study. 
14.4  Study Monitoring  
The study will be monitored in accordance with ICH GCP guidelines. The clinical 
monitor, whether an employee of the Sponsor or its designated representative, has the 
obligation to closely follow the study. In order to fulfil this obligation, the study monitor 
will visit the study centre at periodic intervals, in addition to maintaining necessary 
telephonic and correspondence contact. The clinical monitor will observe current 
personnel knowledge of the study through observation, review of the study records and 
source documentation, as well as discussions with the Investigator and study centre staff. 
Quality assurance auditors, whether employees of the Sponsor or its designated 
representative, may also evaluate the conduct of the study at the study centre at any time 
during or after the study to ensure the validity and integrity of the study data. These 
parties must have access to all study reports and source documentation, regardless of 
location and format. 
Upon completion of the study, the clinical monitor will arrange for a final review of the 
study files, after which the files should be secured for the appropriate time. The 
Investigator, or appointed delegate, will meet with the monitor during the study centre 
visits and co-operate fully in providing the necessary documents for inspection and 
responding to any queries. In addition, the Investigator will permit inspection of study 
files by authorised representatives of the Sponsor or regulatory agencies. The Investigator 
will also allow study-related monitoring audits, Ethics Committee review, and regulatory 
inspection allowing direct access to the source data/documents. 
14.5  Study Closure 
The Investigator reserves the right to terminate the study in the interest of subject welfare. 
The Sponsor may terminate the study at any time. 
Premature termination of the study by any party will be governed under the terms of the 
contract between the parties and the prevailing safety and well-being of patients. 


 
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14.6  Study Record Retention 
In accordance with SI 1928, the Sponsor and the Principal Investigator shall ensure that 
the documents contained, or which have been contained, in the Trial Master File are 
retained for at least 15 years after the conclusion of the study and that during that period 
are: 
• Readily available to the licensing authority on request; and 
• Complete and legible. 
All data derived from the study will remain the property of Kazia Therapeutics Limited. 
The study will be the subject of a final CSR compiled by, or by order of Kazia 
Therapeutics Limited in consultation with the Principal Investigator following the 
guidance in ICH Topic E3. 
All correspondence (e.g. with the Sponsor, Ethics Committee) relating to this study 
should be kept in the appropriate file folders. 
Records of patients’ source documents, eCRF’s, IMP inventory, pertaining to the study 
must be kept on file. Records must be retained according to the current ICH Guidelines 
on GCP. 
The records should be retained by the investigator according to the ICH of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, local regulations, or as 
specified in the Clinical Study Agreement, whichever dictates a longer period. The 
Sponsor shall appoint named individuals within their organisation to be responsible for 
archiving the documents which are, or have been, contained in the Trial Master File. 
Access to those documents shall be restricted to those appointed individuals. If there is 
transfer of ownership of data or documents connected with the clinical study: 
• The Sponsor shall record the transfer; and 
• The new owner shall be responsible for data retention and archiving. 
If the Investigator moves, withdraws from an investigation or retires, the responsibility 
for maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
14.7  Publication Policy 
After completion of the study, the Investigator may prepare a joint publication with the 
Sponsor. The Investigator must undertake not to submit any part of the individual data 
from this protocol for publication without prior consent of the Sponsor at a mutually 
agreed time. 


 
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15  REFERENCES 
 
Alexandre, J., C. Brown, D. Coeffic, N. Raban, J. Pfisterer, J. Maenpaa, H. Chalchal, B. 
Fitzharris, B. Volgger, I. Vergote, C. Pisano, A. Ferrero and E. Pujade-Lauraine (2012). 
CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience 
of the GCIG CALYPSO trial. Br J Cancer 106(4): 633-637 
 
Bendell J. C., Patel M. R., Infante J. R., Kurkjian C. D., Jones S. F., Pant S., Burris 3rd H. 
A., Moreno O., Esquibel V., Levin W. and Moore K. N. (2014). Phase 1, open-label, dose 
escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients 
with refractory solid tumors. Cancer. 121(7):1056-63. 
 
Brown D. M., Heaton A. and Husband A. J. (2008). Idronoxil. Drugs of the Future. 
33(10):844-860. 
 
Cantrixil Investigator’s Brochure, (2016) Version 1.0, July 2016, Kazia Therapeutics 
Limited. 
 
Dizon, D., W. Brady, H. E. Lankes, D. A. Jandial, S. B. Howell, R. J. Schilder, J. H. 
Beumer, S. M. Christner, S. Strychor, M. A. Powell, A. R. Hagemann, K. N. Moore, J. L. 
Walker, P. DiSilvestro and P. M. Fracasso (2015). Results of a phase I pharmacokinetic 
study of intraperitoneal bortezomib (B) and carboplatin (C) in patients with persistent or 
recurrent ovarian cancer (OC): An NRG/Gynecologic Oncology Group study. J Clin 
Oncol 33 (suppl; abstr 5515)  
 
 
Gordon, A. N., M. Tonda, S. Sun and W. Rackoff (2004). Long-term survival advantage 
for women treated with pegylated liposomal doxorubicin compared with topotecan in a 
phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. 
Gynecologic Oncology 95(1): 1-8. 
 
Gourley C., Walker J.L. and Mackay H.J. (2016). Update on Intraperitoneal 
Chemotherapy for the Treatment of Epithelial Ovarian Cancer. American Society of 
Clinical Oncology educational book. 35:143-51. 
 
FDA Guidance 2005, U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) (2005) Guidance for 
Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers.  
 
Fotopoulou C., Vergote I., Mainwaring P., Bidzinski M., Vermorken J. B., Ghamande S. 
A., Harnett P., Prete S., Del A., Green J. A., Spaczynski M., Blagden S., Gore M., 
Ledermann J., Kaye S. and Gabra H. (2014). Weekly AUC2 carboplatin in acquired 
platinum resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of 


 
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platinum cytotoxicity: the phase III OVATURE multicenter randomized study, Annals of 
Oncology. 25:160-65. 
Jaaback, K., Johnson N. and Lawrie T. A. (2011). Intraperitoneal chemotherapy for the 
initial management of primary epithelial ovarian cancer, Cochrane Database of 
Systematic Reviews: CD005340. 
 
Le Tourneau C., Lee J. J., and Siu L.L. (2009). Dose Escalation Methods in Phase I 
Cancer Clinical Trials, Journal of the National Cancer Institute, 101:708-20. 
 
Markman, M., J. Blessing, S. C. Rubin, J. Connor, P. Hanjani and S. Waggoner (2006). 
Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian 
and primary peritoneal cancers: A Gynecologic Oncology Group study. Gynecologic 
Oncology 101(3): 436-440. 
 
Markman, M., K. Webster, K. Zanotti, B. Kulp, G. Peterson and J. Belinson (2003). 
"Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian 
cancer." Gynecologic Oncology 90(3): 593-596  
 
Pant, S., H. A. Burris, 3rd, K. Moore, J. C. Bendell, C. Kurkjian, S. F. Jones, O. Moreno, 
J. G. Kuhn, S. McMeekin and J. R. Infante (2014). A first-in-human dose-escalation study 
of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid 
tumors. Investigational New Drugs 32(1):87-93 
 
Rose, P. G., J. A. Blessing, H. G. Ball, J. Hoffman, D. Warshal, K. DeGeest and D. H. 
Moore (2003). A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal 
carcinoma: a gynecologic oncology group study. Gynecologic Oncology 88(2): 130-135 
 
 
Rustin, G. J., I. Vergote, E. Eisenhauer, E. Pujade-Lauraine, M. Quinn, T. Thigpen, A. du 
Bois, G. Kristensen, A. Jakobsen, S. Sagae, K. Greven, M. Parmar, M. Friedlander, A. 
Cervantes, J. Vermorken and I. Gynecological Cancer (2011). Definitions for response 
and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA-125 
agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 21(2): 
419-423. 
 
Saif, M. W., E. Tytler, F. Lansigan, D. M. Brown and A. J. Husband (2009). Flavonoids, 
phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary 
cancers. Expert Opinions on Investigational Drugs 18(4):469-479. 
 
Sehouli, J., D. Stengel, P. Harter, et al. (2011). Topotecan Weekly Versus Conventional 
5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized 
multicenter phase II trial of the North-Eastern German Society of Gynecological 
Oncology Ovarian Cancer Study Group. J Clin Oncol 29(2):242-248. 
 
Senderowicz A. M. (2010). Information Needed to Conduct First-in-Human Oncology 
Trials in the United States: A View from a Former FDA Medical Reviewer, Clinical 
Cancer Research, 16:1719-25. 


 
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Tewari D., Java J. J., Salani R., Armstrong D.K., Markman M., Herzog T., Monk B.J. and 
Chan J.K. (2015). Long-Term Survival Advantage and Prognostic Factors Associated 
With Intraperitoneal Chemotherapy Treatment in Advanced Ovarian Cancer: A 
Gynecologic Oncology Group Study. Journal of Clinical Oncology, 33:1460-66. 
 
Trimble E. L., and Alvarez R. D. (2006). Intraperitoneal chemotherapy and the NCI 
clinical announcement, Gynecologic Oncology, 103:S18-9. 
 
Walker, J. L. (2013). Intraperitoneal chemotherapy requires expertise and should be the 
standard of care for optimally surgically resected epithelial ovarian cancer patients. 
Annals of Oncology, 24 Suppl 10:x41-45. 
 
Wang, X., R. McKernan, K. H. Kim, A. B. Alvero, A. Whiting, J. A. Thompson, G. Mor, 
M. W. Saif, A. J. Husband, D. M. Brown and E. M. Tytler (2011). Triphendiol (NV-196), 
development of a novel therapy for pancreatic cancer. Anticancer Drugs 22(8):719-731. 
 


 
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16  STUDY SCHEDULE 
The procedures and assessments to be performed during each part of the study are 
outlined in the Schedule of Assessment (Table 4), the Schedule of PK Assessments 
(Table 5) and the Schedule and Assessments in Follow-up (Table 6).  
Actual Cantrixil and chemotherapy administrations and the date and time of study 
assessments will be recorded in the patient’s eCRF. If any abnormalities in safety 
assessments are observed, repeat measurements may be performed at the discretion of the 
Investigator. 
  


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Table 4 
Schedule of Assessments 
 
 
Screening# 
Part A and B: Cycle 1 
Part A and B: Cycles 2 to 8 
Continued 
Access 
 
dOff 
Therapy/ 
End of 
Therapy 
Week 1 
Week 2 
Week 3 
Week 1 
Week 2 
Week 3 
Weeks 
1,2,3 
 
Cantrixil Administration 
 
Day 1 
(+/- 1 day) 
Day 8 
(+/- 1 day) 
Day 15 
(+/- 1 day) 
Day 1 
(+/- 1 day) 
Day 8 
(+/- 1 day) 
Day 15 
(+/- 1 day) 
Days 
1,8,15 
(+/- 1 day) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Catheter/port placement 
Xa 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history, including number, type 
of prior therapies, start and stop dates 
X 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
Xa 
Xa 
X 
X 
X 
X 
X 
 
X 
Physical examination 
Xa 
Xa 
X 
X 
X 
X 
X 
As per 
Standard 
of Care 
X 
Vital signs 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight  
Xa 
Xa 
 
 
X 
 
 
 
Pregnancy testing 
X 
X 
 
 
X 
 
 
X 
ECOG Performance Status 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Safety Laboratory assessmentsf 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
CA-125 Testing 
X 
X 
X 
X 
X 
X 
X 
X 
Urine – dip stick 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Triplicate 12-Lead electrocardiogram 
X 
X 
 
 
X 
 
 
 
AE evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
Radiologic evaluation 
Xb 
 
 
 
 
 
Xb 
As per 
SOC 
Xb 
Tumour measurements 
Xb 
 
 
 
 
 
Xb 
Xb 
Pharmacokinetic studies 
 
Xc 
 
 
Xc 
Xc 
 
 
 
 
Part A 
Screening# 
Part A: Cycle 1 
Part A: Cycles 2 to 8 
 
 
Biomarker Samples – Part A only 
Xe 
 
 
 
Xe 
 
 
 
Xe 
AE: Adverse event; CT: Computed Tomography; ECOG: Eastern Cooperative Cancer Group; MRI: Magnetic Resonance Imaging; PI: Principal Investigator;  


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# The screening period is up to 28 days before the Cycle 1 Day 1 dose of Cantrixil.  
a 
These assessments may coincide, for example if patient already has a port then the pre-study/eligibility assessments may occur on the same day as the first day of 
Cantrixil administration. Otherwise, it is anticipated that there will be a delay between the pre-study/eligibility assessments and the first day of therapy to allow for 
the placement of the port/catheter. 
b 
Radiologic evaluations and subsequent tumour measurements should be conducted at the end of each six-week period, coinciding with the end of each two cycles of 
therapy. The subsequent cycle of therapy should not proceed until this assessment has been evaluated because clear tumour progression may preclude further 
treatment on this study. The PI can use the imaging modality of preference (either MRI or CT) but the same modality must be used for all time-points. 
c 
Pharmacokinetic samples are collected in these weeks per the schedule described in Table 5. 
d 
The “End of Therapy/Off Therapy” assessments may coincide with the assessments performed at one of the other designated time-points. 
e  
Biomarker samples are collected at screening, end of Cycle 2 (most conveniently collected on Day 1 of Cycle 3 before IP administration) and End of Therapy, 
during Part A of the study only. 
f 
Safety assessments as per Section 8.4 and table below. All assessments should be completed on Days 1, 8 and 15 for Parts A and B. 
 
Safety Panel 
Test Parameter 
Haematology 
White blood cell count 
Neutrophils absolute 
 
Red blood cell count 
Lymphocyctes absolute 
 
Haemoglobin 
Monocytes absolute 
 
Haematocrit 
Eosinophils absolute 
 
Mean corpuscular volume 
Basophils absolute 
 
Mean corpuscular haemoglobin 
Platelets 
 
Mean corpuscular haemoglobin concentration 
 
Serum 
Alkaline phosphatase 
Sodium 
biochemistry 
Alanine aminotransferase 
Potassium 
 
Creatine kinase 
Urea 
 
Gamma glutamyl transpeptidase 
Creatinine 
 
Lactate dehydrogenase 
Albumin 
 
Aspartate aminotransferase 
Calcium 
 
Total Bilirubin 
Phosphate 
 
Globulin 
Glucose 
 
Chloride 
Magnesium 
Coagulation 
Activated partial thromboplastin time 
International normalised ratio 
 


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Table 5 
Proposed PK Schedule (Part A and Part B) 
PK 
Time 
Point 
Cycle:Day:Hour:Minutea 
Rationale 
T1 
Cycle 1 
D1 
00:00 (pre-dose) 
Baseline before Cycle 1 
T2 
Cycle 1 
D1 
00:05 
(end 
of 
infusion) 
Samples to measure tmax and t1/2 after first 
monotherapy dose/ first exposure 
T3 
Cycle 1 
D1 
00:30 post-dose 
T4 
Cycle 1 
D1 
01:00 
T5 
Cycle 1 
D1 
02:00 
T6 
Cycle 1 
D1 
04:00 
T7 
Cycle 1 
D1 
06:00 
T8 
Cycle 1 
D2 
24:00  
Process, freeze and batch above samples; ship for analysis on D3 of Cycle 1 (or following 
Monday to avoid weekend arrival at TetraQ) 
T9 
Cycle 3 
D1 
00:00 (pre-dose) 
Check no accumulation after Cycles 1 and 2 
T10 
Cycle 3 
D1 
00:05 (end of 
infusion) 
To facilitate the interpretation of any 
differences seen between Cycle 1/D1 and 
Cycle 3/D8. Without data from Cycle 3/D1, 
we won’t be able to conclude whether 
differences 
between 
Cycle 
1/D1 
and 
Cycle 3/D8 are attributable to repeated 
dosing with Cantrixil or an interaction with 
the combination chemotherapy. 
T11 
Cycle 3 
D1 
00:30 
T12 
Cycle 3 
D1 
01:00 
T13 
Cycle 3 
D1 
02:00 
T14 
Cycle 3 
D1 
04:00 
T15 
Cycle 3 
D1 
06:00 
T16 
Cycle 3 
D2 
24:00+ (before 
combination chemotherapy 
administration) 
Check efficient elimination of Cantrixil 
before 
administration 
of 
combination 
chemotherapy to avoid any drug-drug 
interactions.  
T17 
Cycle 3 
D8 
00:00 (pre-dose) 
Baseline Before Combination Chemotherapy 
Dose 
T18 
Cycle 3 
D8 
00:05 (end of 
infusion) 
Samples to measure tmax and t1/2 after first 
combination therapy dose/ check whether 
combination therapies alter PK 
 
 
T19 
Cycle 3 
D8 
00:30 
T20 
Cycle 3 
D8 
01:00 
T21 
Cycle 3 
D8 
02:00 
T22 
Cycle 3 
D8 
04:00 
T23 
Cycle 3 
D8 
06:00 
T24 
Cycle 3 
D9 
24:00 
Process, freeze and batch above samples; ship for analysis on D10 of Cycle 3 (or following 
Monday to avoid weekend arrival at TetraQ) 
PK: Pharmacokinetics 
a 
A 15-minute window will be allowed for samples taken pre-dose; a 5-minute window will be 
allowed for samples taken up to and including 1-hour post-dose; a 15-minute window for samples 
taken 2 to 6 hours’ post-dose and a 2-hour window for samples taken 24 hours’ post-dose. 
 
 
 
 
 


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Table 6 
Schedule of Assessments in Follow-up 
4* weeks  
follow-up 
8* weeks  
follow-up 
12* weeks 
follow-up 
Concurrent meds 
X 
X 
X 
Physical exam 
X 
X 
X 
Vital signs 
X 
X 
X 
Weight 
X 
X 
X 
Performance Status 
X 
X 
X 
Safety Laboratory 
Assessments 
X 
X 
X 
CA-125 testing  
X 
X 
X 
ECG (if indicated) 
 
 
 
AE evaluation 
X 
 
 
Radiologic evaluationb 
 
Xb 
X 
Tumour measurements 
 
X 
X 
*  
±1 week is acceptable 
AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood Urea 
Nitrogen; CBC: complete blood count; CT: Computed Tomography; ECG: electrocardiogram; LDH: 
Lactate dehydrogenase; LFT: liver function test; MRI: Magnetic Resonance Imaging, SGOT: Serum 
glutamic oxaloacetic transaminase, SGPT: Serum glutamic pyruvate transaminase 
a 
CBC with differentials and platelets, albumin, alkaline phosphatase, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. Include serum urea nitrogen; serum creatinine. 
b 
The Principal Investigator can use the imaging modality of preference (either MRI or CT) but the 
same modality must be used for all time-points; the tumour measurement can be done between 6 
and 8 weeks. 
 


 
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17 PROTOCOL SIGNATURES 
INVESTIGATOR SIGNATURE: 
 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study. I also acknowledge that the Sponsor of the study has the right 
to discontinue the study at any time. I have read the protocol and understand it and will 
work according to it and according to the principles of Good Clinical Practices, applicable 
laws and regulations, and the Declaration of Helsinki. 
 
 
 
 
 
 
Principal Investigator 
 
Date 
<Insert name and qualifications> 
 
<Insert name of institution> 
 
 
 
 
 
 
  
 


 
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SPONSOR SIGNATURE: 
 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study. I also acknowledge that the Investigator has the right to 
discontinue the study at any time. I have read the protocol and understand it and will 
ensure that the clinical trial is conducted according to it and according to the principles of 
Good Clinical Practices, applicable laws and regulations, and the Declaration of Helsinki. 
 
 
 
 
 
 
Sponsor’s Representative 
 
Date 
Dr James Garner 
Chief Executive Officer  
 
 
Kazia Therapeutics Limited 
 
 
 
 


 
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APPENDIX A: STUDY CONTACTS 
PRINCIPAL INVESTIGATOR: 
<insert name title and qualifications> 
 
Tel: 
 
Fax: 
 
Mob: 
 
E-mail:  
 
INVESTIGATIONAL SITE: 
 
Tel: 
 
Fax: 
 
 
24-HOUR MEDICAL CONTACT: 
Dr Kim Strydom, MBChB, HonsBSc, MedSc 
Level 9, 67 Albert Avenue, Chatswood, 
NSW 2067, Australia 
Tel: 
+ 61-(0)2-6653-5013 
Fax: 
+ 61-(0)2-6653-5013 
Mob: 
+ 61-(0)434-651-787 
E-mail: kim.strydom@iqvia.com 
 
SPONSOR REPRESENTATIVE: 
Dr James Garner 
Chief Executive Officer 
Three International Towers 
Level 24, 300 Barangaroo Avenue, Sydney 
NSW 2000, Australia 
Tel: 
+ 61-(0)2-9472-4101 
Fax: 
 
Mob: 
 
E-mail: James.Garner@kaziatherapeutics.com 
 
BIOANALYTICAL ANALYSIS: 
TetraQ 
TetraQ – Research Infrastructure Centre 
The University of Queensland, Level 7, Block 6 
Royal Brisbane & Women's Hospital 
Brisbane QLD 4029 
Australia 
Tel: 
+ 61-(0)7-3365 5115 
Email: 
info@tetraq.com.au 
 


 
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LABORATORY ANALYSIS: 
Genostics Pty Ltd 
 
Tel: 
+61 1300 282 482  
Fax: 
+61 2 8088 7097 
 
 
PHARMACOKINETIC ANALYSIS: 
TetraQ 
TetraQ – Research Infrastructure Centre 
The University of Queensland, Level 7, Block 6 
Royal Brisbane & Women's Hospital 
Brisbane QLD 4029 
Australia 
Tel: 
+ 61-(0)7-3365 5115 
Email: 
info@tetraq.com.au 


 
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APPENDIX B: PROCEDURES FOR THE PLACEMENT OF 
THE INTRAPERITONEAL PORT/ CATHETER AND 
ADMINISTRATION OF INTRAPERITONEAL THERAPY 
This appendix is included as a guideline to aid investigators and does not have to be 
followed explicitly. Each site should rather follow their own standard operating 
procedures for the placement of ports or catheters for intraperitoneal chemotherapy and 
intraperitoneal chemotherapy administration. 
The following device specifications have been adapted from recommendations of the 
Gynaecological Oncology Group recommendations for intraperitoneal chemotherapy: 
“Silicone catheters are preferred. Controversy exists between the use of venous 
9.6 silicone catheters or silicone intraperitoneal ports with fenestrations. Bardport silicone 
peritoneal catheter 14.3 Fr (Reorder number 0603006) that is without a cuff, is the 
preferred intraperitoneal catheter. This has been FDA approved for use in intraperitoneal 
therapy. The 9.6 Fr single lumen intravenous access device, if made with silicone is 
preferred by many surgeons. Brand names are different for different institutions due to 
contracting, and these specifications are intended to be helpful but not limiting. 
Equivalent or similar devices are acceptable if made from silicone, large enough not to 
kink, and without a Dacron cuff. Examples of these include: Bardport MRI Implanted 
Port reorder number 0602680 attachable 9.6 Fr open ended single lumen silicone venous 
catheter. Titanium Dome Implanted Port with attachable 9.6 Fr open ended Single lumen 
venous catheter. Reorder number 0602870. Bard Access Systems 5425 West Amelia 
Earhart Drive Salt Lake City Utah 84116 1-800 545-0890.  
Procedure at the time of a planned laparotomy:  
1. At the completion of the laparotomy just prior to closing the incision, make a 
3 to 4cm incision over the lower costal margin on the side where the catheter is to 
be placed. The incision is carried down to the fascia using blunt and sharp 
dissection.  
2. A subcutaneous pocket superior to the incision is fashioned slightly larger than the 
diameter of the portal.  
3. Select an area several centimetres below and lateral to the umbilicus as the 
peritoneal entrance site of the catheter. Prepare a subcutaneous tunnel from the 
portal pocket to the site in the peritoneal cavity. You want the catheter to enter the 
abdomen; draw the catheter through the subcutaneous tissue into the abdomen 
using a tunnelling device.  
4. Attach the catheter to the portal as per manufacturer’s instructions, and suture the 
portal in place with permanent suture (i.e., 2-0 prolene) to the fascia overlying the 


 
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rib cage. Be sure the chemotherapy nurses will be able to feel the port and 
stabilise it on the chest wall for easy access with Huber needle in the future. Be 
sure the Huber needle will not have to go through the wound to access the port; 
the port should lie superior to the port incision site.  
5. After flushing the system with heparin, 100 units per mL, to determine that flow is 
not obstructed and no leaks exist, place the distal end of the catheter to the desired 
infusion site, with at least 10 cm of free catheter in the abdomen. Do not allow the 
catheter to be long enough to reach the bladder, vagina or rectum.  
6. Close incisions and place a Huber needle trans-dermally into the portal if the 
catheter is going to be irrigated in the immediate postoperative period. Wait a 
minimum of 24 hours prior to treating patient after intraperitoneal port placement, 
and wait for return of gastrointestinal function (regular diet tolerated and normal 
bowel movement) after major laparotomy.  
Surgical implantation with mini lap. (Video available at SGO.org and GOG.org):  
1. Select a site several centimetres below and lateral to the umbilicus and make an 
incision through skin, subcutaneous tissue and fascia. Separate rectus muscle and 
enter peritoneum. Knowledge of the previous surgical resections and current 
anatomy will assist in choosing location.  
2. Pull the catheter from subcutaneous tissue into the peritoneal cavity through the 
full thickness of the abdominal wall (fascia, muscle, peritoneum) from an adjacent 
location (not through the incision) while under direct visualisation to prevent 
injury to bowel. This can be accomplished with a tonsil clamp or tunnelling 
device.  
3. The catheter must be left in the abdominal cavity at least 10 cm to prevent 
migration out of the peritoneal cavity.  
4. The opposite end of the catheter is tunnelled up to the costal margin where it is 
attached to an implanted port as described above. The catheter is left long enough 
to not retract, but not long enough to reach vagina, rectum or bladder. It is 
generally left at least 10 cm into the peritoneal cavity.  
Surgical implantation using laparoscopy:  
1. Laparoscopic placement of an intraperitoneal catheter is usually feasible from a 
left upper quadrant approach. Knowledge of the previous procedures performed 
(i.e. bowel resections and re-anastomosis sites) and location of the tumour will 
inform the surgeon as to the best approach and what locations to avoid.  


 
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2. Once the peritoneal cavity can be visualised, a second puncture can be used to 
gain access to the peritoneal cavity for the catheter, and then the catheter tunnelled 
in the subcutaneous tissues to the planned port pocket.  
Interventional radiology can place intraperitoneal ports in some institutions. This requires 
a great communication between the treating oncologist and the radiologist to get the best 
result. Knowledge of the anatomy and best sites for peritoneal access should be 
communicated. CT or ultrasound directed access to the peritoneal cavity can allow 
catheter placement and then subcutaneous tunnelling to the lower chest wall for 
appropriate port placement and catheter attachment. 
Administration of intraperitoneal therapy: 
Treatment may be administered on an outpatient basis if deemed appropriate by the 
Investigator. To allow for PK sampling, the infusion on Day 1 of Cycle 1 should begin 
early in the day. Scheduling Day 1 to occur on a Monday is ideal, particularly for the later 
cycles, so that dosing visits are always on weekdays.  
Cantrixil must be delivered only via the intraperitoneal route. Cantrixil will be ordered, 
stored, prepared and handled as described in Section 7.1.2. It will be delivered as a saline 
infusion at a dose allocated to the patient upon enrolment. The timing of the preparation 
of Cantrixil is critical. Both Cantrixil and any subsequent distributional infusion must be 
at body temperature before administration. Pharmacy should be notified when the patient 
is present in the infusion suite so that they can prepare any appropriate pre-medications. 
The choice and administration of any pre-medications, including anti-emetics and 
analgesia, should follow local standard operating procedures for intraperitoneal 
chemotherapy. Cantrixil is a CYP450 inhibitor; this must be kept in mind when selecting 
concomitant medications.  
Whilst the pre-medications are being administered, the pharmacy can prepare the 100 mL 
Cantrixil infusion and the extra 1 L saline infusion and warm the solutions according to 
institutional practice, for example using a warm water bath or blood warmer.  
For accession, the patient should be placed supine in semi-Fowler’s position on a 
stretcher, adjustable bed or Gurney. Emla 2.5% cream may be applied to the port site and 
covered with occlusive dressing one hour before accessing the port. The reservoir should 
be accessed under sterile technique, generally using a right-angle, non-coring, 20 gauge, 
1.25-inch gripper-type Huber needle and flushed. A longer needle may be necessary for 
patients with thick subcutaneous tissue on the chest wall. The port should flush easily 
without pain or oedema at the site. Difficult or uncertain accessions can be verified by 
anterior-posterior and lateral radiographs. The needle can then be secured using a 
temporary adhesive dressing. The head of the bed should be raised no higher than 
30 degrees to prevent dislodgement of the needle during infusion. A flat position during 
infusion may cause increased pressure on the diaphragm causing respiratory 


 
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compromise/GI discomfort in patients receiving intraperitoneal infusions. The 100 mL 
Cantrixil solution should be infused first under gravity. Infusion pumps are not 
recommended because they can cause needle dislocation (Hoskins, 2006). Then, to 
facilitate distribution, up to 1 L of warmed normal saline is infused to patient tolerance.  
The position of the needle in the reservoir should be carefully determined and recorded at 
15-minute intervals. Ambulation is restricted as much as possible during infusion to avoid 
dislodgment of the needle. Patients should be encouraged to use the toilet before the 
procedure begins. If the bedpan is required, then the nurse or Investigator should check 
the proper needle position is maintained (GOG). 
The infusion nurse or physician should be aware of and check for the following 
complications which may arise during administration: nausea, vomiting, diarrhoea, 
gastro-oesophageal reflux, pain in the abdomen, chest or port site, excess abdominal 
distention, tenderness, fever, chills, dyspnoea, changes in mental status, tremors, and 
weakness. Most patients will experience some degree of abdominal bloating and 
discomfort during the infusion. The nurse or physician is responsible for determining 
when that discomfort is appropriate to the process and when it signifies that there may be 
a problem. In the former case, the physician or nurse should be able to provide 
reassurance that these sensations are to be expected and will resolve on conclusion of the 
infusion. In the latter, the physician or nurse should be able to quickly and easily notify 
the Principal Investigator of the situation. 
After the infusion is complete, the infusion nurse or physician should reposition the 
patient every 15 minutes for 1 hour in the sequence listed below: 
• 
Head up (30°), 
• 
Slight Trendelenburg, 
• 
Right lateral, 
• 
Left lateral. 
(GOG; Hoskins, 2006). If possible, the bed can also be alternated between the 
Trendelenburg and reverse Trendelenburg positions to facilitate distribution of the 
infusion.  
After removing the Huber needle from the intraperitoneal port site, a pressure dressing 
should be placed over the port site to prevent reflux of the infusion from the port. Patients 
can remove the pressure dressing 12 to 24 hours after intraperitoneal infusion 
References: 
Hoskins, 2006 
Hoskins, P. Intraperitoneal therapy for British Columbia. BC Cancer Agency 
Gynecological Tumour Group (2006) 


 
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GOG 
GOG web-site: GOG Foundation, www.gog.org 
SGO 
SGO web-site: Society for Gynecologic Oncology, www.sgo.org 


 
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APPENDIX C: EVALUATION OF RESPONSE AND 
PROGRESSION USING GYNECOLOGICAL CANCER 
INTERGROUP (GCIG) RESPONSE CRITERIA 
The Gynecological Cancer Intergroup (GCIG) has published a detailed guidance on the 
criteria that could be used in clinical trial protocols to define progression and response in 
recurrent disease using RECIST 1.1 together with the serum marker CA-125 (Rustin et 
al., 2011). The definitions have been validated and the key summary tables have been 
reproduced below for guidance. 
Definition of a Response 
A CA-125 response is defined as at least a 50% reduction in CA-125 levels from a pre-
treatment sample. The response must be confirmed and maintained for at least 28 days. 
Patients are only evaluable if they have a baseline measurement that is at least twice the 
upper limit of normal and with 2 weeks of treatment start. The date when CA-125 levels 
is first reduced by 50% is the date of the CA-125 response.  
To calculate CA-125 responses, the following rules must apply: 
1. Intervening samples and the 28-day confirmatory sample must be less than or 
equal to the previous sample (within an assay variability of 10%).  
2. The same validated assay must be used for each patient 
3. Patients are not evaluable by CA-125 if there has been a medical and/or surgical 
interference with their peritoneum during the previous 28 days. For this study, this 
means that patients are only evaluable for response based on CA-125 levels during 
the Follow-up period. 
CA-125 may be used to evaluate patients without initial measurable disease; 


 
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Table 7 summarises the algorithm for determining the best overall response in patients 
without initial measurable disease and who are evaluable according to the definition 
above. Patients that have measurable disease at study entry can be evaluated during 
Follow-up using both RECIST 1.1 and CA-125 criteria as summarised in Table 8. In 
patients who have measurable disease by both criteria, the date of response will be the 
date of the earlier of the 2 events. 
 


 
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Table 7 Evaluation of Best Overall Response in Patients without Initial Measurable Disease 
and who are Evaluable as proposed by GCIG 
CA-125 
Non-Target 
Lesions* 
New Lesions 
Overall 
Serological 
Response 
Best 
Response 
for this Category 
Also Requires 
Response 
and 
Normalised 
CR 
No 
CR 
Confirmed 
and 
maintained for 28 
days  
Response 
Non-PD 
No 
PR 
Normalised but no 
Response 
Non-CR/Non-PD 
No 
SD 
Non-PR/Non-PD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD# 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*Non-target lesions include ascites and peritoneal thickening, which are not measurable by RECIST 1.1 
#Unequivocal progression in non-target lesions may be accepted as disease progression.  
CR, Complete response; PD, progressive disease; PR, partial response; SD, stable disease 
Table 8 Best Overall Response in Patients with Measurable Disease and who are Evaluable 
by CA-125 as proposed by GCIG 
Target Lesion* 
Non-Target# 
New Lesion 
CA-125 
Overall 
Best 
Response 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR Non-PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR but not normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or NAE 
No 
Not PD 
PR 
NAE 
Non-PD 
No 
PR 
PR 
PD or new >28 days from CA-125 PR^ 
PR 
PR 
SD** 
Non-PD 
No 
PR 
PR 
SD** 
Non-PD or NAE 
No 
Not PR and Not PD 
SD 
PD or new ≤ 28 days from CA-125 PR^ 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
Any 
PD 
Yes or No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Yes or No 
PD 
PD 
*Target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST1.1 
#Non-target lesions include ascites and peritoneal thickening, which are not measurable by RECIST 1.1 
^Patients who have a CA-125 response that occurs more than 28 days from PD according to RECIST 1.1 are considered 
a PR, according to best response, but PD if the RECIST 1.1 PD is within 28 days of CA-125 response. 
**This protocol specifies that the minimum time between 2 measurements for classification of stable disease is 6 weeks.  
CR, Complete response; PD, progressive disease; PR, partial response; SD, stable disease; NAE, not all evaluated; NE, 
Not evaluated. 
 


 
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Definition of Progression 
According to the GCIG progression criteria, patients are not evaluable by CA-125 if there 
has been a medical/or surgical interference with their peritoneum during the previous 28 
days. Hence, during the treatment period of this study, patients will not be defined as 
having progressive disease due to rising CA-125 levels alone. During Follow-up, patients 
may become evaluable for CA-125 and then the definition in Table 10 below may be 
used. In assigning the date of progression, PD by objective tumour size should always 
take precedence over CA-125 should it occur first; although during Follow-up a patient 
may be declared to have PD on the basis of either the objective RECIST 1.1 criteria or the 
CA-125 criteria. The date of progression will be the date of the earlier of the 2 events if 
both are documented.  
Table 9 Definition of Progression as proposed by GCIG 
GCIG Subcategorised Group 
RECIST Measurable/ Non-
measurable 
 
CA-125 
A = Patients with elevated CA-
125 pre-treatment and 
normalisation of CA-125 must 
show evidence of CA-125 
greater than, or equal to, 2 
times the upper limit of the 
reference range on 2 occasions 
at least 1 week apart. 
Compared to baseline (or 
lowest sum while on study if 
less then baseline), a 20% 
increase in sum of diameters 
(RECIST 1.1 definition) 
OR 
Any new lesions (measurable 
or non-measurable) 
OR 
Unequivocal increase in non-
target disease 
Date of PD: date of 
documentation of increase or 
new lesions 
AND/ 
OR 
CA-125 ≥ 2x ULRR 
documented on 2 occasions* 
Date of PD: first date of the 
CA-125 elevation to ≥ 2x 
ULRR  
B = Patients with elevated CA-
125 before treatment, which 
never normalises, must show 
evidence of CA-125 greater 
than, or equal to, 2 times the 
nadir value on 2 occasions at 
least 1 week apart 
As for A 
CA-125 ≥ 2x nadir value on 2 
occasions* 
Date of PD: first date of the 
CA-125 elevation to ≥ 2x nadir 
value 
C = Patients with CA-125 in the 
reference range before 
treatment must show evidence 
of CA-125 greater than, or equal 
to, 2 times the upper limit of the 
reference range on 2 occasions 
at least 1 week apart.  
As for A 
As for A 
*Repeat CA-125 any time but normally not less than 1 week after the first elevated CA-125 level. 
ULRR, upper limit of response range 
 

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Cover Page 
 
Phase I Study of Intraperitoneal Cantrixil in Patients with 
Persistent or Recurrent Ovarian Cancer, Fallopian Tube 
Cancer or Primary Peritoneal Cancer  
 
NCT02903771  
 
Statistical Analysis Plan: V1.2: 05 March 2020 
 
 
 


 
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STATISTICAL ANALYSIS PLAN 
 
 
NVGN-002-101 
PHASE I STUDY OF INTRA-PERITONEAL CANTRIXIL IN PATIENTS 
WITH 
PERSISTENT OR RECURRENT OVARIAN CANCER, FALLOPIAN TUBE 
CANCER OR 
PRIMARY PERITONEAL CANCER. 
 
 
 
 
 
AUTHOR: JISHO JOSE 
VERSION NUMBER AND DATE: V1.2, 05MAR2020 
 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.2 (Dated 05MAR2020) for Protocol NVGN-002-101 Version 4, 30 APR 2018 
 
 
Name 
Signature 
Date 
Author: 
Jisho Jose 
 
05MAR2020 
Position: 
Associate Director - Biostatistics 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
Position: 
 
Company: 
 
 
Approved By: 
 
 
 
Position: 
Clinical and Regulatory Affairs Director 
Company: 
Novogen 
 
 
 


 
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MODIFICATION HISTORY 
 
Unique Identifier 
for this Version 
Date of the 
Document Version 
Author 
Significant Changes from Previous 
Authorized Version 
V1.0 
21JUL2017 
Vishali Vijayanagaram 
Not Applicable – First Version 
V1.1 
24JAN2020 
Jisho Jose 
Latest IQVIA SAP template used  
V1.2 
05MAR2020 
Jisho Jose 
Added the analysis for part A + part 
B combined  
 
 
 


 
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TABLE OF CONTENTS 
F 1. INTRODUCTION ................................................................................................................................... 9 
2. STUDY OBJECTIVES ........................................................................................................................... 9 
2.1. 
Primary Objective ................................................................................................................................... 9 
2.2. 
Secondary Objectives .............................................................................................................................. 9 
2.3. 
Exploratory Objectives ........................................................................................................................... 9 
3. STUDY DESIGN ................................................................................................................................... 10 
3.1. 
General Description .............................................................................................................................. 10 
3.2. 
Schedule of Events ................................................................................................................................. 10 
3.3. 
Changes to Analysis from Protocol ..................................................................................................... 11 
4. PLANNED ANALYSES ....................................................................................................................... 11 
4.1. 
Data Safety Monitoring Committee/Board (DSMC/B) ..................................................................... 11 
4.2. 
Interim Analysis .................................................................................................................................... 11 
4.3. 
Final Analysis ........................................................................................................................................ 11 
5. ANALYSIS SETS .................................................................................................................................. 12 
5.1. 
Maximum Tolerated Dose (MTD) population .................................................................................... 12 
5.2. 
Safety (SAF) population ....................................................................................................................... 12 
5.3. 
Pharmacokinetic (PK) population ....................................................................................................... 12 
5.4. 
Full Analysis population ....................................................................................................................... 12 
6. GENERAL CONSIDERATIONS ........................................................................................................ 12 
6.1. 
Summary statistics ................................................................................................................................ 13 


 
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6.2. 
Treatment Summarization ................................................................................................................... 13 
6.3. 
Precision ................................................................................................................................................. 13 
6.4. 
Reference Start Date and Study Day ................................................................................................... 13 
6.5. 
Baseline ................................................................................................................................................... 14 
6.6. 
Unscheduled Visits Data ....................................................................................................................... 14 
6.7. 
Common Calculations ........................................................................................................................... 14 
6.8. 
Software Version ................................................................................................................................... 14 
7. STATISTICAL CONSIDERATIONS ................................................................................................ 14 
7.1. 
Missing data ........................................................................................................................................... 14 
8. DISPOSITION AND WITHDRAWALS ............................................................................................ 14 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................................... 15 
9.1. 
Derivations ............................................................................................................................................. 15 
10. PROTOCOL DEVIATIONS ................................................................................................................ 16 
10.1. 
Deviations Related to Study Conduct .................................................................................................. 16 
11. DISEASE, SURGICAL PROCEDURE AND MEDICAL HISTORY ............................................. 16 
12. MEDICATIONS .................................................................................................................................... 16 
13. STUDY MEDICATION EXPOSURE ................................................................................................. 17 
13.1. 
Derivations ............................................................................................................................................. 17 
14. PRIMARY OUTCOMES ..................................................................................................................... 17 
14.1. 
Primary Objectives ............................................................................................................................... 17 
15. PHARMACOKINETIC ANALYSIS .................................................................................................. 18 


 
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16. SECONDARY OUTCOMES ............................................................................................................... 19 
16.1. 
Secondary Objectives ............................................................................................................................ 19 
16.1.1. 
Secondary objectives Variables & Derivations ....................................................................................... 19 
16.1.1.1. 
Progression Free Survival ................................................................................................................. 19 
16.1.1.2. 
Time to paracentesis ......................................................................................................................... 20 
16.1.1.3. 
Volume of Malignant Ascites ........................................................................................................... 20 
16.1.1.4. 
Disease Response .............................................................................................................................. 20 
16.1.1.5. 
CA-125 level ..................................................................................................................................... 20 
17. EXPLORATORY OBJECTIVES ....................................................................................................... 21 
17.1. 
Exploratory objectives Variables & Derivations ............................................................................... 21 
17.1.1. 
Circulating Epithelial Tumour Cells ....................................................................................................... 21 
17.1.2. 
Clonogenicity of CETCs ......................................................................................................................... 21 
17.1.3. 
Expression of Stem Cell Markers, CD44 and ALDH ............................................................................. 21 
18. SAFETY OUTCOMES ......................................................................................................................... 21 
18.1. 
Adverse Events ...................................................................................................................................... 22 
18.1.1. 
All TEAEs ............................................................................................................................................... 22 
18.1.1.1. 
Dose Limiting Toxicities .................................................................................................................. 22 
18.1.1.2. 
Severity ............................................................................................................................................. 22 
18.1.1.3. 
Relationship to Study Medication ..................................................................................................... 22 
18.1.2. 
TEAEs Leading to Discontinuation of Study Medication ...................................................................... 23 
18.1.3. 
Serious Adverse Events ........................................................................................................................... 23 
18.1.4. 
Adverse Events Leading to Death ........................................................................................................... 23 
18.2. 
Laboratory Evaluations ........................................................................................................................ 23 
18.2.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA ................ 24 
18.3. 
ECG Evaluations ................................................................................................................................... 24 
18.4. 
Vital Signs .............................................................................................................................................. 25 
18.5. 
Physical Examination ............................................................................................................................ 25 
18.6. 
Eastern Cooperative Oncology Group performance status .............................................................. 26 
18.7. 
Other Analyses ...................................................................................................................................... 26 
19. REFERENCES ...................................................................................................................................... 26 
APPENDIX 1. .................................................. PROGRAMMING CONVENTIONS FOR OUTPUTS


 
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 ................................................................................................................................................................. 26 
Dates & Times ............................................................................................................................................................. 27 
Spelling Format ........................................................................................................................................................... 27 
Listings ......................................................................................................................................................................... 27 
APPENDIX 2. ............................................................................... PARTIAL DATE CONVENTIONS
 ................................................................................................................................................................. 27 
Algorithm for Previous / Concomitant Medications: .............................................................................................. 27 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, and 
safety data for Protocol NVGN-002-101.  It describes the data to be summarised and analysed, including specifics 
of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol Version 4.0, dated Apr 30, 2018. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
• 
To determine the maximum tolerated dose (MTD) of Cantrixil when delivered as a single agent, 
administered intraperitoneally, at a weekly administration frequency. 
• 
To evaluate the safety and tolerability of Cantrixil delivered via intraperitoneal administration as a 
single agent and in combination with standard chemotherapy, when administered weekly. 
• 
To characterise the pharmacokinetics (PK) of intraperitoneal Cantrixil when delivered as a single 
agent and in combination with standard chemotherapy. 
2.2. 
SECONDARY OBJECTIVES 
• 
To evaluate the progression free survival (PFS). 
• 
To evaluate the time to paracentesis and the volume of malignant ascites drained at each paracentesis 
event (for those patients with malignant ascites). 
• 
To evaluate the potential anti-cancer activity of Cantrixil using Response Evaluation Criteria in Solid 
Tumours (RECIST) criteria, version 1.1 and CA-125 measurements. 
• 
To evaluate the change in cancer antigen 125 (CA-125) in peripheral blood before and after 
treatment with Cantrixil. 
2.3. 
 EXPLORATORY OBJECTIVES 
• 
To evaluate the safety, tolerability, PK, and activity of Cantrixil when administered intraperitoneally 
as a single agent and in combination at a twice weekly administration frequency 
• 
To evaluate the change in the number of circulating epithelial tumour cells (CETCs) in peripheral 
blood and malignant ascites (if present) before and after treatment with Cantrixil. 
• 
To evaluate the clonogenicity of CETCs in peripheral blood and malignant ascites (if present) before 


 
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and after treatment with Cantrixil. 
• 
To evaluate the expression of stem cell markers, CD44 and ALDH, in colonies isolated in the 
clonogenicity assays. 
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This study is a progressive design with 2 discrete Parts (Part A: Dose escalation, Part B: Dose expansion). The 
overall study schema is presented in Figure 1 of the protocol. 
3.2. 
SCHEDULE OF EVENTS 
 


 
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3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
The MTD population will include all patients who experienced DLTs in Cycle 1/Part A, as determined by the 
clinical team. The safety, tolerability and MTD data sets regarding the Cycle 1/Part A will be used to determine 
MTD from this analysis population. 
4. ITT POPULATION DEFINITION IN PROTOCOL IS REPLACED WITH 
FULL ANALYSIS POPULATION IN SAP.PLANNED ANALYSES 
The final analyses will be performed for this study. 
4.1. 
DATA SAFETY MONITORING COMMITTEE/BOARD 
(DSMC/B)  
This study will utilise a Data Safety Monitoring Committee/Board (DSMC/B) throughout the study. The 
membership and governance of this committee are outlined in a separate charter. The study SAP will not cover the 
DSMC/B analysis requirement. 
4.2. 
INTERIM ANALYSIS  
There is no interim analysis planned for this study 
4.3. 
FINAL ANALYSIS  
The final analyses will be performed for this study after completion of the study and when all collected data is 
validated, the database will be locked, pursuant to the prior approval by the Sponsor. All details regarding the 
statistical analysis other than PK and the preparation of tables, listings and figures will be described in the 
Statistical Analysis Plan (SAP) prepared by IQVIA and approved by the Sponsor before database lock. 


 
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5. ANALYSIS SETS 
5.1. 
MAXIMUM TOLERATED DOSE (MTD) POPULATION 
The MTD population will include all patients who experienced DLTs in Cycle 1/Part A as determined by clinical 
team. The safety, tolerability and MTD data sets regarding the Cycle 1/Part A will be used to determine MTD 
from this analysis population.  
5.2. 
SAFETY (SAF) POPULATION 
The SAF population will include all enrolled patients who receive at least 1 dose of study treatment. All safety 
analyses will be conducted on this population. 
5.3. 
PHARMACOKINETIC (PK) POPULATION 
The PK population will include all SAF patients who have had at least 1 PK assessment. All PK analyses will be 
conducted on this population. 
5.4. 
FULL ANALYSIS POPULATION 
The Full Analysis Population (FAS) population will include all enrolled patients who receive at least 1 dose of 
study treatment and from whom at least 1 post-baseline efficacy measurement is obtained. All efficacy analyses 
will be conducted on this population and will be based on the actual dose level/single-weekly or twice weekly 
doses of Cantrixil at which each patient has been treated. 
6. GENERAL CONSIDERATIONS 
Derivation of the Pharmacokinetic (PK) parameters and the PK summary figures as well as the statistical analysis 
of the PK variables, will be the responsibility of the clinical pharmacokineticist at TetraQ (The University of 
Queensland, Brisbane, Queensland, Australia).  The efficacy and safety summaries and data listings will be the 
responsibility of the study biostatistician at IQVIA. 
Some minor modifications may be necessary to the planned design of tables, figures, and listings to accommodate 
data collected during the actual study conduct. The changes will be documented in the IQVIA “Changes to 
Planned Statistical Analyses Form”. 


 
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6.1. 
SUMMARY STATISTICS 
For qualitative variables, the population size (N for sample size and n for available data) and the percentage (of 
available data) for each class of the variable will be presented.  Quantitative variables will be summarised using 
descriptive statistics, including number of contributing observations (n), mean, standard deviation (SD), CV, 
median, minimum, and maximum values.   
6.2. 
TREATMENT SUMMARIZATION 
In general, data will be summarised by following groups: 
1. by dose cohort of Part A patients,  
2. All patients in Part B and those in Part A who were treated at the MTD and overall subjects (part A+part B 
subjects combined)  
These two set of subjects are grouped under two columns for analysis. 
6.3. 
PRECISION 
Safety and efficacy variables including derivations thereof, will be reported to the same precision as the source 
data.  
For the reporting of descriptive statistics, the mean will be presented to one digit more precision than the source 
data, whereas standard deviation and standard error will be presented to two digits more precision than the source 
data. The minimum, median, maximum and confidence intervals will be presented to the same precision as the 
source data.   
6.4. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of assessments 
and events.  
Reference start date is defined as the day of the first dose of study medication, (Day 1 is the day of the first dose of 
study medication), and will appear in every listing where an assessment date or event date appears.  
• 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
• 
If the date of the event is prior to the reference date then:  


 
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Study Day = (date of event – reference date). 
6.5. 
BASELINE 
Unless otherwise specified, “Baseline” is defined as the last observed value of the parameter of interest prior to the 
first intake of study medication (this includes unscheduled visits). For numerical variables, change from Baseline 
will be calculated as the difference between the value of interest and the corresponding baseline value. 
6.6. 
UNSCHEDULED VISITS DATA 
Unscheduled measurements will not be included in summary statistics. 
Listings will include all scheduled, unscheduled, retest and early discontinuation data. 
6.7. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
Post-Baseline Value at Visit X – Baseline Value 
6.8. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4. 
7. STATISTICAL CONSIDERATIONS 
7.1. 
MISSING DATA 
No missing data will be imputed. 
8. DISPOSITION AND WITHDRAWALS 
All patients who received study medication will be accounted for in this study. Patient disposition will be tabulated 
with the number of patients who are enrolled, dosed, completed the treatment, completed the study, the reason for 
discontinuation of study and treatment and different population set.  A listing will present dates of completion or 
early withdrawal and the reason for early discontinuation, if applicable, for each patient.   


 
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9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the SAF population. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years)  
• 
Race  
• 
Ethnicity 
• 
Screening Weight (kg) 
• 
Screening Height (cm) 
• 
Screening BMI (kg/m2) 
• 
Childbearing Potential 
• 
ECOG Performance Status 
• 
Tumour Stage at Diagnosis 
• 
Tumour Stage at Study Entry 
• 
Tumour type 
• 
Histological Sub-Type 
• 
Grade 
• 
Breast Cancer Susceptibility Gene (BRCA) Status 
• 
Duration of Disease 
9.1. 
DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Height (m) = height (cm) x 0.010 


 
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• 
Height (m) = height (in) x 0.0254 
• 
Weight (kg) = weight (lb) x 0.45359237  
10. PROTOCOL DEVIATIONS 
Treatment delays of up to three weeks are allowed without being classified as a protocol deviation for Part A, 
Cycle 1. Protocol deviations are not captured in CRF and not analysed. Only a listing from CTMS will be 
provided. 
10.1. 
DEVIATIONS RELATED TO STUDY CONDUCT 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedure 
requirements.  The noncompliance may be either on the part of the patient, the site PI, the study site staff or related 
to study procedures. Any patient enrolled who does not meet eligibility criteria will be considered an enrollment 
deviation.   
11. DISEASE, SURGICAL PROCEDURE AND MEDICAL HISTORY 
Disease history, anti-cancer surgical procedure history, radiotherapy history and previous cancer treatment 
regimens will only be listed as collected in the eCRF for SAF population. 
Patient Medical History information will be presented for the SAF population.  
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central coding 
dictionary version 20.0 
• 
Medical History conditions are defined as past and/or concomitant diseases and reported at Screening.  
• 
Presented by System Organ Class (SOC) and Preferred Term.  
12. MEDICATIONS 
Prior, concomitant and standard chemotherapy medications will be presented for the SAF and coded using World 
Health Organisation (WHO) Drug Dictionary (DD) version WHODDMar2017. The medications will be 
summarised using the WHO Preferred Term. Listings for all reported medications will be provided for the SAF 
population.  
• 
 ‘Prior’ medications are medications which stopped prior to the first dose of Cantrixil. Previous cancer 
treatment regimens along with no of lines will be summarized. Previous platinum therapy (which has the 
word ‘platin’) will be summarized and the time to disease progression after platinum therapy will also be 
analysed. 
• 
‘Concomitant’ medications are medications which  on-going at the time of the first dose or is started after 


 
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the first dose of Cantrixil. 
 
13. STUDY MEDICATION EXPOSURE 
Exposure to study medication in weeks will be presented for the SAF. 
The date of first study medication administration will be taken from the eCRF form. The date of last study 
medication will be taken from the eCRF form.  
Number of Cycles, Total number of cycles, Administered dose by cycle, Total dose administered by cycle, dose 
adjustment with reason and duration of exposure will be summarised descriptively.  
Total Dose administered (mg) = sum over all weeks of actual dose received (mg). 
13.1. 
DERIVATIONS 
Duration of exposure (weeks) = (date of last study medication administration – date of first study medication 
administration + 1)/7  
14. PRIMARY OUTCOMES  
14.1. 
PRIMARY OBJECTIVES 
The primary analysis will be performed on MTD population.  
 For determination of the MTD, individual patient data from the dose escalation part (Cycle 1/Part A) will be 
reported. In addition, for the final statistical analysis, the following will be analysed: 
• 
At each dose level, the number and proportion of patients in the MTD population who 
experience a DLT during the DLT evaluation period (Cycle 1/Part A). Since the number of 
subjects experiencing DLT is less, a listing will be provided. 
• 
At each dose level, the number and proportion of treatment emergent AEs (TEAEs) experienced 
by patients in the MTD population during the DLT evaluation period (Cycle 1/Part A). All the 
events from the first dosing till Cycle 2 Day 1 is considered for DLT evaluation. If Cycle 2 is not 
given then events till 7 days after the last doing in Cycle 1 is considered. 
The MTD will be determined according to the dose-escalation plan (Refer protocol table 3). The MTD is defined 
as the highest dose level at which no more than 1 patient out of 6 patients treated in a cohort and evaluable for 
DLT determination experiences a DLT during Part A/ Cycle 1. 


 
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15. PHARMACOKINETIC ANALYSIS   
        The PK assessment results will be described in a PK study report prepared by TetraQ at completion of the study 
 
 
 
 
 


 
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16. SECONDARY OUTCOMES  
16.1. 
SECONDARY OBJECTIVES 
The secondary analyses will be performed on ITT population. 
16.1.1. 
SECONDARY OBJECTIVES VARIABLES & 
DERIVATIONS 
16.1.1.1. 
Progression Free Survival 
The progression free survival (PFS) will be summarised as mentioned in section 6.2. Details of the calculation of 
progression free survival and censoring rules are presented below. 
PFS (in months) is defined as the time from first dose to the date of first disease progression as defined by 
RECIST version 1.1 and/or Gynecological Cancer Intergroup (GCIG) criteria  or death from any cause (whichever 
occurs first). If a patient has neither disease progression nor died, PFS will be censored on the date of the last 
disease assessment (from end of study form or visit form whichever is the maximum). PFS (in months) is 
calculated as follows: 
PFS = (date of event/censoring - date of first dose + 1) / 30.4375 
 
 
Date of event /censoring 
Censoring 
Disease progression /Death 
Date of disease assessment/ 
Death Date 
No 
No assessment available but progression was specified as 
reason for study/treatment discontinuation 
Date of discontinuation 
No 
No progressive disease 
No disease response 
assessment after the first 
dose and no progression 
specified at study 
discontinuation 
Date of discontinuation 
 
 
 
Yes 
No disease response 
assessment after the first 
dose and patient is alive at 
study discontinuation 
Date of discontinuation 
 
 
 
Yes 
Otherwise 
Date of last disease assessment 
Yes 
Kaplan-Meier (KM) estimates of the median time to event and the corresponding two-sided 95% confidence 
interval will be presented along with the estimates for the 25th and 75th percentiles and the associated ranges 
(minimum, maximum).  The survivor function will be displayed graphically using a Kaplan-Meier curve. If the no 
of censored is more than 50% of the subjects, then the medial estimate will not be considered as realiable. 


 
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16.1.1.2. 
Time to paracentesis 
The time to paracentesis will be measured as the time from the first recorded paracentesis event until the next 
paracentesis event for malignant ascites drainage. The time between all subsequent paracentesis events in the 
sequence for each patient with malignant ascites will also be recorded. The first recorded paracentesis event may 
be immediately before the first dose of Cantrixil but this may not be true for all patients.  
The overall number of paracentesis events will be summarised and changes in frequency during the period of 
treatment for each patient described.  
The graph to be plotted will depict any changes in the frequency of paracentesis events by illustrating the  
normalised change in time between events vs event (n). The time between the first recorded paracentesis event and 
the next one will be set at “1” then all subsequent tim te between events will be normalised to this “baseline”.  
16.1.1.3. 
Volume of Malignant Ascites 
The volume of abdominal fluid will be measured by estimating the volume of malignant ascites drained at each 
paracentesis event and the normalized volume to “baseline” will be summarised as mentioned in section 6.1. 
“Baseline” will be the volume recorded at the first paracentesis event captured, this may be immediately before the 
first dose of Cantrixil but not necessarily. This “baseline” volume will be set at “1” and all subsequent volumes 
normalised to this “baseline”.  
The graph to be plotted will depict the normalised volume at each event vs event (n) for each patient with 
malignant ascites. 
16.1.1.4. 
Disease Response 
Disease response will be measured using RECIST version 1.1 criteria; during Follow-up, response may be also 
assessed using the GCIG response criteria that incorporates CA-125 measurements. 
The disease response within the time from start of treatment till end of the study will be considered. The disease 
response for target lesions, non-target lesions, CA-125 response and overall response will be summarised as 
mentioned in section 6.1 using frequency and percentage of patients in each response category. 
Best overall response will be derived using the protocol Table 8 algorithm for determining the best overall 
response in patients without initial measurable disease and who are evaluable per the definition above. Patients 
that have measurable disease at study entry can be evaluated during Follow-up using both RECIST 1.1 and CA-
125 criteria as summarised in protocol Table 9. In patients who have measurable disease by both criteria, the date 
of response will be the date of the earlier of the 2 events. Overall Response assessment using RECIST and GCIG 
at scheduled visits and Best overall response at the end of trial using RECIST and GCIG will be summarised 
descriptively and listed. 
16.1.1.5. 
CA-125 level 
Concentration of CA-125 in peripheral blood will be assayed in local laboratories using locally validated assays at 
baseline and then weekly during treatment, at the End of Therapy and during Follow-up. CA-125 level will be 
summarised using descriptive statistics as mentioned in section 6.1. 


 
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17. EXPLORATORY OBJECTIVES 
17.1. 
EXPLORATORY OBJECTIVES VARIABLES & DERIVATIONS 
The first exploratory objectives to evaluate safety, tolerability, PK, and activity of Cantrixil when administered 
intraperitoneally as a single agent and in combination at a twice weekly administration frequency will be 
summarised same as explained in primary, secondary and safety objectives analysis methods. Other objectives will 
be summarised as follows: 
17.1.1. 
CIRCULATING EPITHELIAL TUMOUR CELLS 
Enumeration of CETC in peripheral blood and malignant ascites (if present) will be assayed using the 
MAINTRAC® CETC Count method by Genostics or similar methodology. This method uses a fluorochrome-
labelled antibody against surface epithelial antigen (EpCam) to tag CETCs. Image analysis allows CETC numbers 
to be calculated in relation to blood volume over the course of treatment. Samples will be assayed at baseline, at 
the end of Cycle 2 and at the End of Therapy.   
Number of circulating epithelial tumour cells (CETCs) in peripheral blood and malignant ascites (if present) 
before and after treatment with Cantrixil will be summarised descriptively and listed for the FAS population. 
17.1.2. 
CLONOGENICITY OF CETCS 
Clonogenicity of CETCs in peripheral blood and malignant ascites (if present) will be measured using the 
MAINTRAC® Tumour Sphere Units assay by Genostics or similar methodology. Samples will be assayed at 
baseline, at the end of Cycle 2 and at the End of Therapy. Clonogenicity of CETCs will be summarised 
descriptively and listed for the ITT population.  
17.1.3. 
EXPRESSION OF STEM CELL MARKERS, CD44 AND 
ALDH 
Expression of stem cell markers in the isolated colonies will be measured using labelled antibodies and scanning 
fluorescent microscopy techniques by Genostics or similar facility. A descriptive summary and listing of patients 
with stem cell markers ALDH1 and CD44 (%) and number of colonies and number of colonies positive per mL of 
blood and/or per CETC for a stem cell marker will be summarised descriptively. 
18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the safety population.  


 
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There will be no statistical comparisons for safety data. 
18.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 
18.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity during or 
after the first dose of Cantrixil. 
An overall summary of number of patients within each of the categories described in the sub-section below will be 
provided as specified in the templates.  
Listings will include TEAEs and non-TEAEs, including event start/stop date/time, onset day, severity, seriousness, 
relationship to investigational product, action taken and outcome. 
18.1.1.1. 
Dose Limiting Toxicities 
A listing of patients presenting DLTs occurring during Cycle 1/Part A will be summarised by SOC and PT for the 
groups mentioned in the section 6.2. The MTD determining set will be used. 
18.1.1.2. 
Severity 
Severity of AEs will be graded using the National Cancer Institute (NCI)-CTCAE version 4.03 severity grading 
scale. 
If a patient reports a TEAE more than once within that SOC/ PT, the TEAE with the worst case severity will be 
used in the corresponding severity summaries. 
18.1.1.3. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as ‘Yes’ or ‘No’ to the question: ‘Do you consider that 
there is a reasonable possibility that the event may have been caused by the study treatment?’. TEAEs with a 
missing relationship to study medication will be regarded relationship as ‘Yes’.  If a patient reports a TEAE more 
than once within that SOC/ PT, the TEAE with the worst-case relationship will be used in the corresponding 
relationship summaries. 
 


 
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18.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY 
MEDICATION 
TEAEs leading to Study Discontinuation are those events which are recorded on the AE eCRF where the End of 
Study eCRF Primary Reason for Premature Discontinuation is ‘Adverse Event,’ and the AE Number matches the 
AE eCRF.  A listing of AEs leading to study discontinuation will be prepared. 
18.1.3. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the Adverse 
Event eCRF. A summary of serious TEAEs by SOC and Preferred Term will be presented by dose cohort and 
twice weekly dose cohort. 
18.1.4. 
ADVERSE EVENTS LEADING TO DEATH 
AEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be presented by dose. 
18.2. 
LABORATORY EVALUATIONS 
Results from the safety laboratory will be included in the reporting of this study for the assessments given in the 
protocol section 8.4 
Presentations will use SI Units.  
 
The following summaries will be provided for laboratory data: 
 
• 
Actual and change from baseline (for quantitative measurements) 
• 
Incidence of abnormal values according to normal range criteria 
• 
Shift from baseline according to abnormal criteria (for quantitative measurements and categorical 
measurements) 
• 
Listing of patients with the actual measurements by each lab category/parameters  
• 
Listing of patients meeting markedly abnormal criteria for each lab category/parameter 


 
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18.2.1. 
 LABORATORY REFERENCE RANGES AND 
MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges by the lab 
vendors and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
Clinical laboratory reference/normal ranges will be listed.  Lab data with ‘<’ or ‘>’ symbols along with the results 
cannot be interpreted and hence cannot be included in the analysis. 
18.3. 
ECG EVALUATIONS 
Results from Electrocardiogram (ECG) will be included in the reporting of this study.  
 All time point recordings will be obtained in triplicate.  Only average of these records will be displayed in the 
listing and used in tables. 
 
The following ECG parameters will be reported for this study: 
• 
Ventricular Rate (bpm) 
• 
PR Interval (msec) 
• 
QRS Duration (msec) 
• 
QT Interval (msec) 
• 
RR Interval (msec) 
• 
QTcF (msec)  
• 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (ANCS) 
o 
Abnormal, Clinically Significant (ACS) 
 


 
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The following summaries will be provided for ECG data for the groups mentioned in section 6.1.: 
• 
Actual and change from baseline for each cycle (for quantitative measurements) 
• 
Listing of patient ECG data. 
 
18.4. 
VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (bpm) 
• 
Respiratory Rate (resp/min) 
• 
Body Temperature (⁰C) 
• 
Weight (kg) 
The following summaries will be provided for vital signs data by dose cohort and twice weekly dose cohort. 
• 
Actual and change from baseline for each cycle 
• 
Listing of patient vital signs data  
18.5. 
PHYSICAL EXAMINATION   
The following Physical Examination measurements per investigator’s judgment will be reported for this study as 
collected on the Physical Examination (PE) eCRF unless otherwise specified below: 
• 
General Appearance 
• 
Head 
• 
Ears  
• 
Eyes  
• 
Nose 
• 
Throat 
• 
Respiratory system (chest) 
• 
Cardiovascular system 
• 
Gastrointestinal/ Liver  


 
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• 
Musculoskeletal/Extremities 
• 
Dermatological/Skin 
• 
Thyroid/Neck 
• 
Lymph Nodes 
• 
Neurological/Psychiatric 
• 
Other 
 
The following summaries will be provided for physical examination data for the groups mentioned in section 6.2. 
Incidence of Normal, Abnormal, Not Done at all the collected weeks. 
 
A listing with all data collection at various visits along with abnormality details will also be presented. 
18.6. 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Eastern Cooperative Oncology Group (ECOG) performance status (Grade 0 - Grade 5) will be for the groups 
mentioned in section 6.2 by presenting the number and percentage of patients in each category for the safety 
population.  
18.7. 
OTHER ANALYSES 
A listing of patients who had a closed catheter or port inserted will be presented for the data collected from the 
port insertion eCRF page. 
A list of patients with the pregnancy report will be presented for the data collected in the eCRF. 
Tumour measurements for target lesions sum of diameters will be summarised using descriptive statistics for 
actual and change from baseline at the scheduled assessments for the groups mentioned in section 6.2. 
Tumour measurements for non-target lesions will only be listed by patient. 
19. REFERENCES 
NA 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
 
IQVIA Output Conventions 


 
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Outputs will be presented according to the following Global Bios > Processes > GBIOS Processes - 
Implementation Guidelines and Templates > General Guidelines and Templates > Output Conventions.   
 
DATES & TIMES 
Depending on data available, dates will take the form yyyy-mm-dd.  
 
SPELLING FORMAT 
English US (or English UK)  
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Part A followed by Part A. Under Part A, subjects will be sorted by the ascending order of dose group 
assigned to.  
• 
center-subject ID,  
• 
date (where applicable), 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. ) For cases where start dates are stop dates are missing, they 
will be presented as '-/-' 
ALGORITHM FOR PREVIOUS / CONCOMITANT MEDICATIONS:  
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post study  


 
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START 
DATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 


 
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For time to disease progression after previous platinum therapy calculation, if the date part of treatment end regimen is partial i.e 
only date unknown, then it will be considered as 15thof that month for the calculation of time to disease proression after platinum 
therapy.