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Trial registered on ANZCTR


Registration number
ACTRN12613000302752
Ethics application status
Not yet submitted
Date submitted
12/03/2013
Date registered
19/03/2013
Date last updated
14/02/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I study of Dz13 drug targeting the c-Jun gene in subjects with melanoma skin cancer
Scientific title
A phase I/Ib study to determine the safety and tolerability of Dz13 DNAzyme targeting c-Jun, administered to subjects with in-transit or satellite melanoma metastases via single intra tumoural injections of 100 mcg twice weekly
Secondary ID [1] 282041 0
Nil
Universal Trial Number (UTN)
U1111-1139-9983
Trial acronym
DISCOVER 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
in-transit or satellite melanoma 288496 0
Condition category
Condition code
Cancer 288844 288844 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dz13 DNAzyme (100 mcg) complexed with lipids DOPE and DOTAP administered as single intra-tumoural injection twice weekly to cohort 1(total dose 200 mcg) for one week cycle, to cohort 2 for two weeks (total dose 400 mcg) and to cohort 3 for three weeks (total dose 600 mcg as the dose finding Part 1. Part 2 fourth expanded cohort will receive Dz13 DNAzyme (100 mcg) complexed with lipids DOPE and DOTAP administered as single intra-tumoural injection twice weekly for two or three week cycles. Selection of two or three week treatment duration will be dependent on the following conditions as assessed from cohorts 2 and 3 in Part 1:
1. acceptable saftey profile following review of all safety data by a Data Safety Monitoring Board (DSMB) and pharmacokinetic (PK) analysis
2. evidence of c-Jun (Dz13 treatment target gene) suppression in tumour tissue and/or evidence of tumour response change in tumour size
Intervention code [1] 286631 0
Treatment: Drugs
Comparator / control treatment
No control treatment
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288973 0
To assess the safety and tolerability of Dz13 (complexed with DOPE/DOTAP) when administered to subjects with either in-transit or satellite melanoma metastases via single intra-tumoural injections of 100 mcg twice weekly from 1 week escalating to 2 and 3 week dosing cycles by adverse events (AEs), changes in vital signs, changes in clinical laboratory tests, changes in 12- lead electrocardiography (ECG).

Pre-clinical animal studies indicate some skin irritation following injection which was more likely attributable to the lipid component of study drug and thus injection site reaction reactions may be an expected AE. In a previous Phase 1 study of single intra-tumoural injection of up to 100 mcg Dz13 in BCC skin tumours, there no drug related serious AEs or clinically significant changes in laboratory safety parameters or ECG. Pharmacokinetic (PK) analysis indicated no detectable levels of systemic Dz13 up to 28 days post treatment.

Emergent AEs that might be treatment related was reported by one subject and included injection site discomfort, swelling, wound infection, nausea and blurred vision; two subjects reported phlebitis and erythema all of which were all mild and resolved.

Monitoring of AEs and PK analysis will continue to be conducted for this next Phase I/Ib study of multiple intra-tumoural injections of Dz13 up to a maximum of six 100 mcg doses over three weeks.
Timepoint [1] 288973 0
1, 3, 6, 24 hours per injection day (2 days/1 week cycle), 4, 10, 14, 25 and 32 days post last injection for cohort 1.
3, 24 hours per injection day (4 days/2 week cycle), 4 14, 25 and 32 days post last injection for cohort 2.
3, 24 hours per injection day (6 days/3 week cycle), 4 14, 25 and 32 days post last injection for cohort 3.
Primary outcome [2] 288974 0
To determine whether six 100 mcg doses given as three week cycle has an acceptable safety profile and can be recommended for use in Phase II studies.
Assessment monitored by adverse events according to CTCAE version 4.0), changes in vital signs, clinical laboratory tests and 12-lead ECG. Safety will be evaluated by Data Safety Monitoring Board (DSMB) at the completion of each dose cohort and on an ad-hoc basis following any dose limiting toxicities.
Timepoint [2] 288974 0
3, 24 hours per injection day (6 days/3 week cycle), 4 14, 25 and 32 days post last injection for cohort 3.
Secondary outcome [1] 301474 0
To measure serum levels of Dz13 following administration of twice weekly doses of 100 mcg Dz13 complexed with DOPE and DOTAP via intra-tumoural injection commencing with two injections (1 week cycle) up to a maximum of six injections (3 week cycle).
Timepoint [1] 301474 0
1, 3, 6, hours per injection day (2 days/1 cycle), 10, 25 and 32 days post last injection for cohort 1.
3 hours per injection day (4 days/2 cycles), 14, 25 and 32 days post last injection for cohort 2.
3 hours per injection day (6 days/3 cycles), 14, 25 and 32 days post last injection for cohort 3.
Secondary outcome [2] 301475 0
To compare melanoma tumour histopathology and immunohistochemistry 14 days following administration of Dz13 relative to baseline of directly treated and untreated "bystander" lesions.
Timepoint [2] 301475 0
14 days post last injection day.
Secondary outcome [3] 301476 0
To compare melanoma tumour size of treated and lesions 4 and 14 days following Dz13 administration relative to baseline and to compare melanoma tumour size of "bystander" untreated lesion 14 days following Dz13 administration relative to baseline.

Tumour lesions will be measured in two dimensions by calipers and Solarscan digital dermoscopy imaging
Timepoint [3] 301476 0
4 and 14 days

Eligibility
Key inclusion criteria
Diagnosed dermal in-transit or satellite metastatic melanoma with at least 3 measurable lesions at minimum distance of 5 cm from each other
ECOG performance status 0-1
Acceptable haematologic, coagulation, renal and hepatic function
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Metastatic/in-transit or satellite lesions located on face, head and neck
Women of child bearing age
Prior or co-existing malignancy
Radiotherapy to >30% bone marrow in previous 3 months
Clinically significant non-malignant disease
Current immunosuppression
History of immune-mediated throbocytopenia or other platelet disease
Enrolment in another clinical study involving any other investigational agent

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)
Allocation is not concealed. Subject enrolled into cohorts in sequential order
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Study is not randomised
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Other
Other design features
Dose escalation Part 1: doses cohorts will receive Dz13 injections twice weekly for one week (Cohort 1) , two weeks (Cohort 2 ) and three weeks (Cohort 3). Expansion Part 2 dose cohort will receive Dz13 100 mcg injections twice weekly two weeks (2 cycles) or three weeks (3 cycles) dependent of safety profile and molecular signals of intra tumoural efficacy as determined from Part 1. Each subject will have 3 identified lesions, one control untreated lesion excised pre-Dz13 injection, treated lesion and an untreated "bystander" lesion excised post Dz13 injection.
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data from escalation Part 1 will be presented in a descriptive manner. Continuous measures will be summarised and tabulated using counts (n), mean, standard deviation (SD), median, minimum and maximum. Categorical measures will be summarised and tabulated using counts (n) by frequencies and percentage. The 95% confidence intervals will be provided.
Plasma concentrations of Dz13 will be expressed in ng/mL with defined Lower Limit of Quantification (LLOQ) of 1.0 ng/mL. Plasma concentrations of Dz13 will be summarised and tabulated by measurement, cohort and overall.
The primary efficacy measure in expanded cohort Part 2 will be response in tumoural c-Jun expression. c-Jun expression values prior to and following treatment, and the changes noted, will be summarised and tabulated.
Tumour size measures and molecular tumoural characteristics prior to and following treatment, and the changes noted, will be summarised and tabulated by cohort and overall for Cohorts 1, 2 and 3 as secondary efficacy endpoints
A mixed models repeated measures analysis will be performed to determine if there are differences in c-Jun expression response across the tumour lesions (control, treated and 'bystander' untreated) and will also be used to analyse tumour size change in all tumours (control, treated and "bystander" untreated) as secondary efficacy endpoints.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
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] 707 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 6452 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 286832 0
Government body
Name [1] 286832 0
Cancer Institute NSW
Address [1] 286832 0
Australian Technology Park
Suite 101
1 Central Avenue
Everleigh NSW 2015
Country [1] 286832 0
Australia
Primary sponsor type
University
Name
The University of New South Wales
Address
Sydney
NSW 2052
Country
Australia
Secondary sponsor category [1] 285622 0
None
Name [1] 285622 0
Address [1] 285622 0
Country [1] 285622 0
Other collaborator category [1] 277313 0
University
Name [1] 277313 0
University of Sydney
Address [1] 277313 0
Sydney
NSW 2006
Country [1] 277313 0
Australia
Other collaborator category [2] 277314 0
Other Collaborative groups
Name [2] 277314 0
Melanoma Institute of Australia
Address [2] 277314 0
40 Rocklands Rd
Wollstonecraft
NSW 2065
Country [2] 277314 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 288898 0
Sydney Local Health District (SLHD) Ethics review Committee (RPAH Zone)
Ethics committee address [1] 288898 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 288898 0
Australia
Date submitted for ethics approval [1] 288898 0
27/03/2013
Approval date [1] 288898 0
Ethics approval number [1] 288898 0
EC001134

Summary
Brief summary
This study aims to test the safety of multiple injections of the Dz13 (combined with DOPE and DOTAP) drug in patients with melanoma skin cancer.

Dz13 is a small piece of DNA which binds to an mRNA molecule c-Jun and cuts it into two pieces disrupting the production of the c-Jun protein and can lead to a reduction in growth and spread of the tumour.

Who is it for?
You may be eligible to join this study if you are aged 18 years or more, and have been diagnosed with dermal in-transit or satellite metastatic melanoma. You should have at least 3 measurable lesions at minimum distance of 5 cm from each other.

Trial details:
There will be 4 different cohorts (or groups) in this study, who are enrolled consecutively. Participants in the first group will receive 2 injections of the drug Dz13 into their tumour over a period of 1 week. Participants in the second group will receive twice weekly injections of Dz13 for two weeks, and group three for three weeks. Based on the findings of the first three groups, the fourth group will then receive twice weekly Dz13 injections for two or three weeks.

All participants will be regularly assessed to determine safety and tolerability of treatment. The treated and pre-seelcted untreated tumours will be assessed by investigating the c-Jun levels within the tumour tissue and measuring tumour size. It is thought that Dz13 treatment may reduce the size of melanoma tumours in humans without significant toxicity.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38218 0
Dr Catriona McNeil
Address 38218 0
Royal Prince Alfred Hospital
Sydney Cancer Centre,
Level 5, Gloucester House
Missenden Road
Camperdown NSW 2050
Country 38218 0
Australia
Phone 38218 0
+61 2 9519 5894
Fax 38218 0
+61 2 9519 1546
Email 38218 0
Catriona.McNeil@sswahs.nsw.gov.au
Contact person for public queries
Name 38219 0
Prof Levon Khachigian
Address 38219 0
Centre for Vascular Research
Lowy Building, Level 3
University of New South Wales
Sydney 2052
Country 38219 0
Australia
Phone 38219 0
+61 2 9385 2537
Fax 38219 0
+61 2 9385 1797
Email 38219 0
l.khachigian@unsw.edu.au
Contact person for scientific queries
Name 38220 0
Prof Levon Khachigian
Address 38220 0
Centre for Vascular Research
Lowy Building, Level 3
University of New South Wales
Sydney 2052
Country 38220 0
Australia
Phone 38220 0
+61 2 9385 2537
Fax 38220 0
+61 2 9385 1797
Email 38220 0
l.khachigian@unsw.edu.au

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