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Trial registered on ANZCTR


Registration number
ACTRN12618000941268
Ethics application status
Approved
Date submitted
22/03/2018
Date registered
4/06/2018
Date last updated
4/06/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Safety, tolerability, and pharmacokinetics of single and multiple doses of a PLA2 inhibitor (c2) in men with prostate cancer: A Phase 0 and limited dose-escalation trial
Scientific title
Safety, tolerability, and pharmacokinetics of single and multiple doses of a PLA2 inhibitor (c2) in men with prostate cancer: A Phase 0 and limited dose-escalation trial
Secondary ID [1] 294434 0
None
Universal Trial Number (UTN)
NA
Trial acronym
PLA001
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 307180 0
Condition category
Condition code
Cancer 306294 306294 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are 2 parts to this study

Part I: Single dose

All eligible patients will receive oral c2 tablet for single does (Part I).
c2 ( at the assigned dose) will be administered as a single oral dose at the start of a 14 day observation period for patient 1 in each cohort. Subsequent patients within the cohort will be enrolled after safety review of patient 1 by the DSMB.

At each dose level, beginning with Dose Level 1, three patients will be initially enrolled. If none of the first 3 patients experiences a dose-limiting toxicity (DLT) then dose escalation will proceed to the next dose level. If one DLT is encountered in the first 3 patients in that dose level, then up to another 3 patients will be enrolled at that level. If another DLT occurs in that cohort, dose escalation will stop and Dose Level -1 (previous dose level) will be used for Part 2.
Otherwise, dose escalation will proceed to the next dose level.

The next dose level will be determined by agreement of the investigators and DSMB when all patients at the current dose level have completed 14 days of continuous dosing

Dose Escalation Schedule

Dose Level 1: 5 mg - 50% target dose
Dose Level 2: 10 mg -100% target dose
Dose Level 3: 40 mg - 400% target dose
Dose Level 4: 100 mg - 1000% target dose

Part II: oral c2 at a maximum of 10 mg daily, for a total of up to 6 weeks

On completion of the observation period (14 days for each patient) for the cohort, the
DSMB will conduct a safety review meeting to determine whether the cohort can Progress to Part 2.

For repeat dosing (Part 2) participants will visit the hospital weekly for review of adverse events, physical examination and laboratory tests. A weekly supply of trial drug will dispensed by the Liverpool Cancer Therapy pharmacy at each visit. Participants will also be provided with a patient diary to record any possible adverse events
,
Intervention code [1] 300725 0
Treatment: Drugs
Comparator / control treatment
NONE
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305296 0
(i) To determine preliminary safety and tolerability of c2 in patients with advanced prostate cancer.

- participants will visit the hospital weekly for review of adverse events, physical examination and laboratory tests to determine preliminary safety and tolerability of c2
Timepoint [1] 305296 0
All patients who are treated with c2 will be evaluated for safety.
All patients who have received c2 and have at least four measured c2 levels over a 24 hr
period will be included in the pharmacokinetic analysis.
Secondary outcome [1] 344778 0
To explore single and multiple dose pharmacokinetics of c2 in patients with advanced
prostate cancer
Samples will be assayed using a validated LC-MSMS assay

the pharmacokinetic parameters being assessed Cmax:Maximum plasma concentration, Tmax: Time at which Cmax was achieved, also read directly from the raw data. T½: Terminal elimination half-life = ln 2/ke
Timepoint [1] 344778 0
In Part 1, blood samples for pharmacokinetic analyses will be collected for all
participants according to the following schedule: pre-dosing, 30 mins, 60 mins (1 hour),
120 mins (2 hours), 180 mins, 240 mins (4 hours), 360 mins (6 hours) and 24 hours

In Part 2, limited pharmacokinetic sampling will be conducted at baseline (T0) and 2 hrs
after dosing on the first day of continuous daily dosing, then again on day 8, 15, 22 and
43.
Secondary outcome [2] 347608 0
Serum PSA
Timepoint [2] 347608 0
PSA will be measured within 7 days prior to dosing and approximately every 3 weeks for
the duration of the study.
Secondary outcome [3] 347609 0
Urinary hGIIA
Timepoint [3] 347609 0
Change in urinary hGIIA levels will be determined over the duration of the study time period

Eligibility
Key inclusion criteria
1. At least 18 years of age.
2.Have provided written informed consent.
3.Evidence of prostate cancer: ( Biopsy evidence of adenocarcinoma of the prostate)
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
5.Adequate organ function as follows:
• Bone Marrow Reserve: absolute neutrophil count (ANC) equal to 1.5 x 109/L; platelet count equal to 100 x 109/L; haemoglobin equal to 9.0 g/dL.
• Hepatic: bilirubin equal to 1.5 times the upper limit of normal (× ULN), alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT) equal to 3.0 × ULN (AP, AST, and ALT equal to 5 × ULN is acceptable if liver has tumor involvement).
6.Anticipated adequate venous access for pharmacokinetic sampling
7.Continuing androgen-ablative therapy without changes in prior 1 month
8.Documented metastatic disease
9.Male participants if sexually active agree to use highly effective methods of
contraception for the period of the study, and for 90 days after the last day of
treatment.
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1.Treatment within the last 30 days with a drug that has not received regulatory approval at the time of study entry.
2.Anti-tumour therapy (including chemotherapy, radiation therapy, targeted therapeutics or hormonal therapy) within the 30 days prior to first study therapy. Permitted exceptions are concurrent use of GnRH agonists or oral anti-androgens for prostate cancer at stable doses for at least 30 days prior to study entry.
3.Serious concomitant disorders (for example, heart failure) at the investigator’s discretion.
4.Presence of an uncontrolled, active infection requiring therapy (at the investigator’s discretion).
5.Central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy).
6.Inability to comply with protocol or study procedures.
7.ECOG performance status 2, 3 or 4.

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)
NA
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
NA
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
NA
Phase
Phase 0
Type of endpoint(s)
Safety
Statistical methods / analysis
All patients who are treated with c2 will be evaluated for safety.
All patients who have received c2 and have at least four measured c2 levels over a 24 hr
period will be included in the pharmacokinetic analysis.
Change in PSA will be determined from baseline to the end of study. Change in urinary
hGIIA levels will be determined over the duration of the study time period. Screeningand investigatrion for other potential biomarkers will be undertaken at a later date from
stored biospecimens (blood, urine).

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
Recruitment hospital [1] 10470 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 22179 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 299062 0
Charities/Societies/Foundations
Name [1] 299062 0
Prostate Cancer Foundation of Australia
Address [1] 299062 0
Level 3, 39-41 Chandos St
St Leonards NSW 2065
Country [1] 299062 0
Australia
Primary sponsor type
Individual
Name
Prof Paul de Souza
Address
Cancer Therapy Centre, Liverpool Hospital, Elizabeth Street Liverpool2170
Country
Australia
Secondary sponsor category [1] 298297 0
None
Name [1] 298297 0
NA
Address [1] 298297 0
NA
Country [1] 298297 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299996 0
South Western Sydney Local Health District Human Research Ethics Commiittee
Ethics committee address [1] 299996 0
Liverpool Hospital, Elizabeth Street Liverpool NSW 2170
Ethics committee country [1] 299996 0
Australia
Date submitted for ethics approval [1] 299996 0
29/08/2016
Approval date [1] 299996 0
06/02/2018
Ethics approval number [1] 299996 0
HE16/056

Summary
Brief summary
This is a first-in-human study of a new PLA2 inhibitor drug called c2.

Who is it for?
You may be eligible for this study if you are 18 or older and have prostate cancer confirmed by biopsy.

Study details
All participants in this study will receive the study drug (called c2), which is an oral pill. In the first part of the study, volunteers will be divided into 4 cohorts, each taking a different single dose of the medication. In the second part of the study, participants will take at a maximum of 10mg the study drug. Participants will be monitored for adverse events and medication efficacy, and provide blood and urine for analysis.

It is hoped this research will provide evidence about this medication and lay the groundwork for future studies of this drug.
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 82206 0
Prof Paul de Souza
Address 82206 0
Cancer Therapy Centre, Liverpool Hospital No1 Elizabeth street Liverpool NSW 2170
Country 82206 0
Australia
Phone 82206 0
+612 8738 9744
Fax 82206 0
+612 8738 9205
Email 82206 0
Paul.deSouza@health.nsw.gov.au
Contact person for public queries
Name 82207 0
Miss Jennifer Aung
Address 82207 0
Cancer Therapy Centre, Liverpool Hospital No1 Elizabeth street Liverpool NSW 2170
Country 82207 0
Australia
Phone 82207 0
+61 2 8738 9163
Fax 82207 0
+61 2 8738 9205
Email 82207 0
Jennifer.Aung@health.nsw.gov.au
Contact person for scientific queries
Name 82208 0
A/Prof Kieran F. Scott
Address 82208 0
Ingham Institute , 1 Campbell street Liverpool 2170
Country 82208 0
Australia
Phone 82208 0
+61 2 8738 9026
Fax 82208 0
+61 2 8738 9205
Email 82208 0
Kieran.Scott@westernsydney.edu.au

No information has been provided regarding IPD availability
Summary results
No Results