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Trial registered on ANZCTR


Registration number
ACTRN12617001573347
Ethics application status
Approved
Date submitted
24/10/2017
Date registered
22/11/2017
Date last updated
2/11/2018
Date data sharing statement initially provided
2/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Clinical study investigating the safety PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer
Scientific title
An open-label, multi-centre Phase Ib study of the safety and tolerability of IV infused PG545 in combination with nivolumab in patients with advanced solid tumours with an expansion cohort in patients with metastatic pancreatic cancer
Secondary ID [1] 293195 0
ZU545102
Secondary ID [2] 293198 0
CA209-9KJ
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced solid tumours 305195 0
Pancreatic Cancer 305196 0
Condition category
Condition code
Cancer 304511 304511 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1: Dose escalation in patients with advanced or metastatic solid tumours: PG545 25, 50 or 100 mg once weekly via IV infusion and Nivolumab 240 mg every two weeks via IV infusion. Patients receive weekly doses of PG545 according to the cohort to which they are assigned. A standard 3+3 cohort design is employed for each cohort. Intrasubject escalation to the next highest dose is allowed once the next highest dose has been demonstrated to be tolerated.
Stage 2: Expansion phase in patients with metastatic pancreas tumour: Recommended PG545 dose from Stage 1 once weekly via IV infusion and Nivolumab 240 mg every two weeks via IV infusion.

Treatment to continue until disease progression or withdrawal due to tolerability. Patients will be treated at site ensuring treatment compliance.
Intervention code [1] 299451 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303748 0
Stage 1: Determine the maximum tolerated dose (MTD) of once-weekly intravenously administered PG545 in combination with intravenously administered nivolumab (240 mg every two weeks) in subjects with advanced solid tumours, as defined by dose limiting toxicity. The MTD is determined using dose limiting toxicities (DLTs) assessed by the treating physician, using NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. DLT toxicities also include the development of positive anti-heparin antibody, and an inability to complete the first dosing cycle due to any toxicity thought to be associated with the test drug.
Timepoint [1] 303748 0
28 days post treatment commencement.
Primary outcome [2] 303750 0
Stage 2: To assess the safety and tolerability of weekly administration of PG545 in combination with nivolumab in patients with metastatic pancreatic cancer. Outcome is assessed by clinical examination and blood tests.
Timepoint [2] 303750 0
Weekly for the duration of the study.
Secondary outcome [1] 340066 0
To assess the safety and tolerability of weekly administration of PG545 in combination with nivolumab in patients with advanced solid tumours cancer. Outcome is assessed by clinical examination and blood tests.
Timepoint [1] 340066 0
Weekly for the duration of the study.
Secondary outcome [2] 340067 0
To measure anti-tumour activity in response to weekly administration of PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer, using RECIST v1.1 criteria.
Timepoint [2] 340067 0
Every two 28-day cycles for the duration of the study.
Secondary outcome [3] 340068 0
To measure anti-tumour activity in response to weekly administration of PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer, using immune-related response criteria (irRC).
Timepoint [3] 340068 0
Every two 28-day cycles for the duration of the study.
Secondary outcome [4] 340069 0
To assess the biological activity of weekly PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer, by analysing relevant biomarkers of immunomodulation in the peripheral blood. This is an exploratory outcome.
Timepoint [4] 340069 0
Week 1 and week 4 of the first 28-day cycle.
Secondary outcome [5] 340070 0
To assess the anti-tumour activity in response to weekly administration of PG545 in combination with nivolumab by measuring CA 19-9 in patients with metastatic pancreatic cancer.
Timepoint [5] 340070 0
Day 1 of each 28-day cycle.
Secondary outcome [6] 340629 0
To assess the biological activity of weekly PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer, by analysing relevant biomarkers in the tumour microenvironment (TME). This is an exploratory outcome.
Timepoint [6] 340629 0
Week 1 and week 4 of the first 28-day cycle.

Eligibility
Key inclusion criteria
Stage 1
1. Histological or cytological documentation of non haematological, malignant solid tumour, excluding primary brain or spinal tumours.
2. Subjects with advanced solid tumours who have experienced failure of all standard therapies, no longer are candidates for standard therapy, have no standard therapy available, or choose not to pursue standard therapy (the latter is to be documented).
Stage 2:
1. Histologically- or cytologically-proven metastatic adenocarcinoma of the pancreas.
2. Patient’s acceptance to have a tumour biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator). The lesion to be biopsied cannot be used as a target lesion for RECIST assessment.
General
3. Age 18 years and older.
4. Measurable disease (at least 1 target lesion) according to RECIST v1.1.
5. Life expectancy of at least 12 weeks.
6. ECOG Performance Status of 0 or 1.
7. Understand, sign and date informed consent to participate in study.
8. Able and willing to meet all protocol-required treatments, investigations and visits.
9. Have adequate organ function including: Bone Marrow Reserve: Absolute neutrophil count (ANC) not less than (NLT) 1500 cells/µL, platelets NLT 100,000/µL, haemoglobin N 9 g/dL; Hepatic: Bilirubin not more than (NMT) 1.5 x upper limits of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) NMT 2.5 x ULN (AST and ALT <5 times if liver metastases are present); Renal: > 60 mL/minute creatinine clearance (Cockroft and Gault equation); Coagulation: Activated partial thromboplastin time (APTT) NMT 1.2 x ULN and International Normalised Ratio (INR) NMT 1.4.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Stage 2:
1. Subjects who have received more than one prior chemotherapy regimen.
General
2. Clinically significant non-malignant disease including, but not limited to, hepatitis B or C, major surgery within 6 weeks of enrolment, active clinically significant infection, myocardial infarction within 6 months prior to enrolment, cerebrovascular event or transient ischaemic attack within 6 months prior to enrolment, or a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents).
3. Clinically significant gastrointestinal bleeding within 4 weeks prior to enrolment or clinically-significant bleeding from the tumour within 4 weeks prior to enrolment.
4. Anti-cancer therapy within 4 weeks of Cycle 1 day 1 (excluding GnRH agonists for prostate cancer) or five times the half-life of the agent (if shorter).
5. Palliative radiation for bone metastases within 2 weeks of Cycle 1 day 1.
6. Active or prior CNS metastases.
7. Subjects who have received prior immune checkpoint targeting drugs (e.g., anti PD1, and PDL1, anti-KIR, anti CD137, etc)
8. Subjects with uncontrolled hypertension (defined as either resting systolic > 150 mmHg or resting diastolic > 100 mmHg; as measured at screening (average of three measurements).
9. History of allergy and/or hypersensitivity and/or other clinically significant adverse drug reaction to heparin or other anti-coagulant agents, or to any monoclonal antibody.
10. History of immune-mediated thrombocytopaenia or other platelet abnormalities or other hereditary or acquired coagulopathies, or laboratory evidence of anti-heparin antibodies, or any previous history of having tested positive for anti-heparin antibodies.
11. Use of heparin within two weeks prior to enrolment. Patients already receiving low molecular weight heparin (LMWH) compounds who have tested negative for anti-heparin antibodies at screening may be enrolled and continue LMWH therapy.
12. Patients on immunosuppressive agents except for systemic prednisone (or equivalent) of NMT 10 mg/day.
13. History of severe allergic, anaphylactic or other significant adverse reaction to radiographic contrast media (iodinated or non-iodinated), which cannot be managed by pre treatment with agents such anti histamines, and which, in the opinion of the Investigator, renders the subject unsuitable for routine CT or MRI scanning. Subjects who are contra-indicated for CT or MRI scanning for other reasons (e.g. ferromagnetic implants, profound claustrophobia), should not be enrolled.
14. Autoimmune disorders or any other pre-existing immunodeficiency condition (including known HIV infection).
15. Women who are pregnant or breast-feeding.
16. Women of child-bearing potential and male subjects who are partners of women of childbearing potential who are unable or unwilling to practice a highly effective means of contraception. Effective birth control includes: a) birth control pills, depot progesterone, or an intrauterine device plus one barrier method, or b) two barrier methods. Effective barrier methods are: male and female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Women of child-bearing potential must practice a highly effective means of contraception for at least 5 months post last treatment; men for at least 7 months post last treatment.
17. Active substance abuse, including alcohol, which, in the opinion of the Investigator, risks impairing the ability of the subject to comply with the protocol.
18. Subjects who have received an investigational agent within 28 days prior to Cycle 1 Day 1 or five times the half-life of the investigational agent (if shorter); or are currently participating in any other clinical study or research project which involves administration of a pharmaceutical product or experimental treatment, or which involves protocol-specified laboratory tests, imaging studies or other investigations.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 12345 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 12346 0
The Alfred - Prahran
Recruitment hospital [3] 12347 0
Northern Cancer Institute - St Leonards
Recruitment postcode(s) [1] 24586 0
5000 - Adelaide
Recruitment postcode(s) [2] 24587 0
3004 - Prahran
Recruitment postcode(s) [3] 24588 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 297825 0
Commercial sector/Industry
Name [1] 297825 0
Zucero Pty Ltd
Address [1] 297825 0
184 Moorabool Street, Geelong, Vic, 3220.
Country [1] 297825 0
Australia
Funding source category [2] 297826 0
Commercial sector/Industry
Name [2] 297826 0
Bristol-Myers Squibb Australia Pty Ltd
Address [2] 297826 0
Level 2, 4 Nexus Court, Mulgrave, Vic 3170.
Country [2] 297826 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Scientia Clinical Research Limited
Address
Levels 5 and 6, The Bright Building, Corner High and Avoca St, Randwick, NSW, 2031.
Country
Australia
Secondary sponsor category [1] 296866 0
None
Name [1] 296866 0
Address [1] 296866 0
Country [1] 296866 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298879 0
CALHN Research Ethics
Ethics committee address [1] 298879 0
Ethics committee country [1] 298879 0
Australia
Date submitted for ethics approval [1] 298879 0
Approval date [1] 298879 0
16/06/2017
Ethics approval number [1] 298879 0
Ethics committee name [2] 301838 0
Bellberry Limited
Ethics committee address [2] 301838 0
129 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [2] 301838 0
Australia
Date submitted for ethics approval [2] 301838 0
Approval date [2] 301838 0
Ethics approval number [2] 301838 0

Summary
Brief summary
This study will determine the safety and tolerability of PG545 in combination with Nivolumab in patients with advanced solid tumours or metastatic pancreatic cancer.

Who is it for?
You may be eligible to join this study if you are aged 18 years old or above and have a non- haematological, malignant solid tumour (for Stage 1) or metastatic adenocarcinoma of the pancreas (for Stage 2).

Study details
This study has two stages: Stage 1 to establish the maximum tolerated weekly dose of PG545 intravenous (IV) infusion in combination with fortnightly Nivolumab IV infusion, and stage 2 to safety and tolerability of the recommended dose from stage 1 of PG545 IV infusion in combination with fortnightly Nivolumab IV infusion. Treatment in both stages will continue until disease progression, unacceptable toxicity or participant withdrawal.

Participants will be regularly assessed throughout the study in order to monitor safety and tumour response.

It is envisaged that the combination of PG545 and Nivolumab will improve on the limited treatment options currently available for patients with pancreas cancer. Once demonstrated to be safe, the combination can then be explored in larger clinical studies in pancreas cancer and other tumour types.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78534 0
Prof David Goldstein
Address 78534 0
Scientia Clinical Research, Bright Building, Level 5, Corner of High & Avoca Streets, Randwick, Sydney NSW 2031
Country 78534 0
Australia
Phone 78534 0
+61 (02) 93825800
Fax 78534 0
Email 78534 0
contactus@scientiaclinicalresearch.com.au
Contact person for public queries
Name 78535 0
Ms Lesley Clement
Address 78535 0
Scientia Clinical Research, Bright Building, Level 5, Corner of High & Avoca Streets, Randwick, Sydney NSW 2031
Country 78535 0
Australia
Phone 78535 0
+61 (02) 93825800
Fax 78535 0
Email 78535 0
contactus@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 78536 0
Mr Keith Dredge
Address 78536 0
Zucero Pty Ltd, 184 Moorabool Street, Geelong, Victoria
Country 78536 0
Australia
Phone 78536 0
+61 (07) 32739133
Fax 78536 0
Email 78536 0
keith.dredge@zucero.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
The implications of sharing have not been discussed by the sponsor or funding companies to date.
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable