Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000842066
Ethics application status
Approved
Date submitted
24/06/2010
Date registered
6/10/2010
Date last updated
8/06/2021
Date data sharing statement initially provided
8/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1/2 Study of Valproate in Combination with Interferon alpha in Relapsed, Recurrent or Progressive Neuroblastoma
Scientific title
A Phase 1/2 Study to define the objective response rate of Paediatric Patients with Relapsed, Recurrent or Progressive Neuroblastoma to Valproate in Combination with Interferon alpha
Secondary ID [1] 252094 0
ACCT003

Australian and New Zealand Children's Haematology and Oncology Group
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed, Recurrent or Progressive Neuroblastoma 257648 0
Condition category
Condition code
Cancer 257819 257819 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Course 1: Interferon: 3 MU/m2 subcutaneous (SC) given 3 times per week. Valproate: commence at 10 mg/kg/day, increase weekly until trough level reaches 525-700 micromoles/L.

Courses 2-12: Interferon: 3 MU/m2 SC given 3 times per week. Valproate: dose to maintain trough at 525-700 micromoles/L

Mode of administration: Valproate - oral, Interferon - subcutaneous injection

Treatment duration is 12 courses. Due to the time required for dose escalation to reach desired concentration range, Course 1 may be significantly longer than 28 days. Interferon therapy will continue throughout Course 1, whatever its length. All subsequent treatment courses will be 28 days in duration.
Intervention code [1] 256717 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 258682 0
To define the objective response rate of relapsed/refractory neuroblastoma patients to the combination interferon alpha and valproic acid.

All imaging modalities that showed any abnormality at commencement of therapy will be repeated to evaluate response. Imaging modalities include metaiodobenzylguanidine (MIBG) scan, computerised tomography (CT) scan / magnetic resonance imaging (MRI) scan, bone scane, bone marrow aspirate. Response Evaluation Criteria in Solid Tumours (RECIST) will be used for patients with solid tumours. Patients with bone marrow disease will be assessed on morphologic evidence of neuroblastoma by routine H and E staining. Patients who have a positive MIBG san at the start of therapy will be evaluable for MIBG response.
Timepoint [1] 258682 0
Interim analysis of response rate will be performed after 15 patients have been assessed for tumour response. If at least 2 objective tumour responses are seen, a further 10 patients will be enrolled and response rate analysied for all 25 patients.
Patients will be re-evaluated for response every 8 weeks until disease progression. In addition to a baseline scan, confirmatory scans should also be obtained at least four weeks following initial documentation of objective response.
Secondary outcome [1] 264698 0
To evaluate the toxicities of the combination treatment of interferon alpha and valproic acid.
The National Cancer Institute Common Toxicity Criteria (NCI-CTC) V3.0 will be used to classify and grade the intensity of adverse events and their relationship to study drug administration.
Timepoint [1] 264698 0
All patients will be evaluable for toxicity from the time of their first treatment.
Adverse events are to be recorded at every cycle during treatment and 30 days post last study drug administration.
Secondary outcome [2] 264699 0
To assess the effects of the combination treatment on time to disease progression.
All imaging modalities that showed any abnormality at commencement of therapy will be repeated to evaluate response. Imaging modalities include MIBG, CT/MRI, bone scane, bone marrow aspirate. Response Evaluation Criteria in Solid Tumours (RECIST) will be used for patients with solid tumours. Patients with bone marrow disease will be assessed on morphologic evidence of neuroblastoma by routine H and E staining. Patients who have a positive MIBG san at the start of therapy will be evaluable for MIBG response.
Overall response will be defined using The International Neuroblastoma Response Criteria. The International Neuroblastoma Response Criteria were developed to define responses in patients being treated for neuroblastoma with frontline therapy. These were utilized as a basis for the following response criteria, which integrate response at all sites defined as measurable in this study, including CT/MRI lesions which meet RECIST criteria, MIBG positive lesions, and bone marrow disease. These criteria will be used to define the overall response for the patient in the statistical analysis.
Timepoint [2] 264699 0
Patients will be re-evaluated for response every 8 weeks until disease progression.
Secondary outcome [3] 264700 0
To assess the effects of combination treatment on overall survival.
Outcomes will be assessed at clinic visits.
Timepoint [3] 264700 0
Patients will be followed up after the completion of treatment to determine overall survival for up to 5 years following completion of treatment.
Secondary outcome [4] 264701 0
To measure the effect of interferon alpha and valproic acid on angiogenesis.
Blood will be sent to Professor Marshall's laboratory at the Children's Cancer Institute Australia (CCIA), prior to treatment, and prior to Cycle 3 for anti-angiogenic markers and endothelial cell inhibitory studies.
Timepoint [4] 264701 0
Blood samples are collected prior to treatment and prior to Cycle 3.

Eligibility
Key inclusion criteria
Target tumour is neuroblastoma.
Patient must have one of the following:
- recurrent disease following aggressive multidrug frontline chemotherapy and autologous transplantation
- resistent/refractory disease during aggressive multidrug frontline chemotherapy
Patients must have measurable disease
Patients must have a performance level of 0, 1, or 2 using Karnofsky scale or Lansky scale
Patients must have a life expectancy of greater than or equatl to 8 weeks
Patients must have fully recovered from the actue toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering the study
Patients must have adequate organ function
Minimum age
No limit
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with recurrent or progressive benign lesions without viable malignant neuroblastoma
Patients do not meet concomitant medication restrictions
For female patients, pregnancy and breast feeding
Myeloplastic syndrome
Uncontrolled infection

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)
Eligible patients will enrolled in 2 cohorts. Stage 1, 15 patients evaluable for toxicity will be accrued. Stage 2, an additional 10 patients will be accrued.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/12/2010
Actual
17/06/2011
Date of last participant enrolment
Anticipated
Actual
28/05/2015
Date of last data collection
Anticipated
3/02/2016
Actual
8/11/2016
Sample size
Target
25
Accrual to date
Final
9
Recruitment in Australia
Recruitment state(s)
NSW,VIC,QLD,SA,WA
Recruitment outside Australia
Country [1] 2723 0
New Zealand
State/province [1] 2723 0
Auckland

Funding & Sponsors
Funding source category [1] 257197 0
Self funded/Unfunded
Name [1] 257197 0
Country [1] 257197 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Children's Haematology and Oncology Group
Address
PO Box 5418 Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 256452 0
None
Name [1] 256452 0
Address [1] 256452 0
Country [1] 256452 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259226 0
The Royal Alexandra Hospital for Children HREC
Ethics committee address [1] 259226 0
Ethics committee country [1] 259226 0
Australia
Date submitted for ethics approval [1] 259226 0
07/07/2010
Approval date [1] 259226 0
03/02/2011
Ethics approval number [1] 259226 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31333 0
Dr David Ziegler
Address 31333 0
Sydney Children's Hospital High St Randwick NSW 2031
Country 31333 0
Australia
Phone 31333 0
+612 9382 1730
Fax 31333 0
Email 31333 0
d.ziegler@unsw.edu.au
Contact person for public queries
Name 14580 0
Helen Mueller
Address 14580 0
Sydney Children's Hospital
High St
Randwick NSW 2031
Country 14580 0
Australia
Phone 14580 0
+612 9382-1980
Fax 14580 0
+612 9382 1789
Email 14580 0
Helen.Mueller@SESIAHS.HEALTH.NSW.GOV.AU
Contact person for scientific queries
Name 5508 0
David Ziegler
Address 5508 0
Sydney Children's Hospital
High St
Randwick NSW 2031
Country 5508 0
Australia
Phone 5508 0
+612 9382 1730
Fax 5508 0
+612 9382 1789
Email 5508 0
d.ziegler@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.