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Trial registered on ANZCTR
Registration number
ACTRN12618000321246
Ethics application status
Approved
Date submitted
21/02/2018
Date registered
5/03/2018
Date last updated
21/02/2023
Date data sharing statement initially provided
19/02/2019
Type of registration
Prospectively registered
Titles & IDs
Public title
A Phase II Study of Panobinostat in Paediatric, Adolescent and Young Adult Patients with Solid Tumours Including Osteosarcoma, Malignant Rhabdoid Tumour/Atypical Teratoid Rhabdoid Tumours and Neuroblastoma.
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Scientific title
A Phase II Study of Panobinostat in Paediatric, Adolescent and Young Adult Patients with Solid Tumours Including Osteosarcoma, Malignant Rhabdoid Tumour/Atypical Teratoid Rhabdoid Tumours and Neuroblastoma.
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Secondary ID [1]
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ACCT008
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Secondary ID [2]
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ASSG35
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Secondary ID [3]
303305
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CLBH589XAU13T
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Universal Trial Number (UTN)
U1111-1208-4010
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Trial acronym
NORTH
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Linked study record
Phase I study: ACTRN12609000978268
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Health condition
Health condition(s) or problem(s) studied:
Osteosarcoma
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Malignant Rhabdoid Tumour
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Neuroblastoma
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Atypical Teratoid/Rhabdoid Tumour (AT/RT)
306723
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Condition category
Condition code
Cancer
305424
305424
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0
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Children's - Other
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Cancer
305929
305929
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0
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Children's - Brain
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Cancer
305930
305930
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0
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Bone
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
This is an open label, phase II, multicentre study evaluating the anti-tumour activity of continuous, low dose of panobinostat in patients with refractory solid tumours stratified by primary histology into osteosarcoma, malignant rhabdoid tumour/atypical teratoid rhabdoid tumour (MRT/ATRT), and neuroblastoma.
Patients will be stratified at study entry by tumour type into 3 strata: osteosarcoma, neuroblastoma and MRT/ATRT.
Patients will be enrolled onto the study following completion of their conventional therapy including chemotherapy and/or radiation treatment and completion of a three-week wash out period.
Panobinostat will then be administered as a continuous daily oral dose (starting at 10mg/m2 per day), for up to a year. Minimum dose is 2mg/m2 per day, maximum dose is 16mg/m2 per day. Dosing will follow a dose de-escalation or escalation scheme for each stratum which will be determined by biological effect of the drug (measured in patient peripheral blood samples) and levels of toxicity (measured by dose limiting toxicity and adverse event observed). Dose levels for subsequent enrolments in each strata will be based on the de-escalated or escalated dose in each cohort. The final dose per strata will be that which achieves significant biological effect with acceptable toxicity that is maintained for a 4 week period.
Participants (or their parent/guardian) will be required to maintain a daily drug dosing form to monitor drug usage throughout the trial.
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Intervention code [1]
300152
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Treatment: Drugs
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Comparator / control treatment
No Control Group
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
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Efficacy as measured by Clinical Benefit Rate (percentage of patients with stable disease or better using MRI/CT imaging)
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Assessment method [1]
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Timepoint [1]
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Every 2 months for 12 months after intervention commencement (primary timepoint is 4 months)
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Primary outcome [2]
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Safety, as assessed by laboratory evaluations, electrocardiograms, physical examination, measurement of vital signs, performance status and body weight. Adverse events will be graded according to the NCI-CTCAE, version 4.0
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Assessment method [2]
304577
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Timepoint [2]
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Weekly for 1 month and then monthly for 12 months after intervention commencement
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Secondary outcome [1]
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Clinical Benefit Rate: Percentage of patients with stable disease or better using functional imaging (MIBG or FDG-PET).
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Assessment method [1]
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Timepoint [1]
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Every 2 months for 12 months after treatment commencement
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Secondary outcome [2]
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Time to progression calculated as the time from registration to date of event defined as the first documented progression or death resulting from underlying cancer.
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Assessment method [2]
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Timepoint [2]
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2 years after completion of treatment
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Secondary outcome [3]
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Overall Survival calculated as the time from registration to date of death
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Assessment method [3]
342448
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Timepoint [3]
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2 years after completion of treatment
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Eligibility
Key inclusion criteria
- Patients must be < 40 years of age.
- Patient must have been histologically diagnosed with osteosarcoma, neuroblastoma or MRT/ATRT at time of diagnosis or relapse. (Osteosarcoma and neuroblastoma arms are closed to recruitment).
- Patient disease is refractory to conventional therapy, in the case of osteosarcoma, neuroblastoma and MRT/ATRT or there is an absence of effective conventional therapy available in the case of ATRT. Patients must have stable disease (SD) or better following treatment with salvage therapy.
- Karnofsky performance level greater than or equal to 60% for patients 16 years of age and greater, OR Lansky performance levels greater than or equal to 60% for patients less than 16 years of age.
- Life expectancy of greater than 8 weeks.
- Fully recovered from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to entering study.
- Patients with CNS tumours who are receiving dexamethasone are on a stable/decreasing dose for at least 1 week.
- Adequate BM function
- Adequate renal function
- Adequate liver function
- Adequate cardiac function
- Adequate pulmonary function
- Adequate CNS function – seizure free for at least 2 months
- Adequate serum calcium, magnesium and potassium concentrations
- If female and post-menarchal, pregnancy test must be negative.
- If of reproductive potential, have agreed to use effective contraceptive method.
- If female and lactating, have agreed not to breastfeed.
- Patient and/or their legal guardian have signed a written informed consent form.
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Minimum age
No limit
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Maximum age
39
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Have received myelosuppressive chemotherapy and/or biologic therapy within 3 weeks (4 weeks if prior nitrosourea).
- Have received local palliative radiotherapy within 2 weeks.
- Have received craniospinal radiotherapy within 3 weeks.
- Have received greater than or equal to 50% radiation of the pelvis within 6 weeks.
- Have received other substantial BM radiation within 6 weeks.
- Have received growth factor(s) within 1 week.
- Are receiving enzyme inducing anticonvulsant therapy.
- Are receiving medications associated with prolongation of QTc interval
- Are receiving hydrochlorothiazide.
- Are receiving metronidazole and/or disulfiram
- Have uncontrolled sepsis.
- Have previously received panobinostat.
- Have symptoms of congestive heart failure, uncontrolled cardiac rhythm disturbance, or a QTc greater than or equal to 450msec.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
The target enrolment is 20 participants per strata: 1) Osteosarcoma, 2) Neuroblastoma and 3) MRT/ATRT.
The study will employ a Simon two-stage minimax design (Simon, et al , 1989). Stage 2 will proceed if disease stability at 4 months is observed in three or more of the first nine patients in that strata and less than 30% of patients experience a dose limiting toxicity at the final dose level.
The Clinical Benefit Rate (percentage of participants with stable disease or better) will be calculated with a 95% CI. Time to progression (TTP) will be calculated as the time from registration to date of event defined as the first documented progression or death resulting from underlying cancer. TTP and Overall Survival will be estimated by the Kaplan-Meier survival analysis.
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Recruitment
Recruitment status
Active, not recruiting
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Date of first participant enrolment
Anticipated
2/04/2018
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Actual
9/01/2019
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Date of last participant enrolment
Anticipated
1/08/2021
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Actual
20/01/2022
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Date of last data collection
Anticipated
21/12/2024
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Actual
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Sample size
Target
60
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Accrual to date
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Final
25
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
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Recruitment hospital [1]
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The Royal Childrens Hospital - Parkville
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Recruitment hospital [2]
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Sydney Children's Hospital - Randwick
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Recruitment hospital [3]
9885
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The Children's Hospital at Westmead - Westmead
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Recruitment hospital [4]
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Womens and Childrens Hospital - North Adelaide
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Recruitment hospital [5]
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John Hunter Children's Hospital - New Lambton
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Recruitment hospital [6]
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Monash Children’s Hospital - Clayton
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Recruitment hospital [7]
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [8]
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Princess Alexandra Hospital - Woolloongabba
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Recruitment hospital [9]
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Queensland Children's Hospital - South Brisbane
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Recruitment hospital [10]
13198
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [11]
13199
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The Chris O’Brien Lifehouse - Camperdown
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Recruitment hospital [12]
18523
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Perth Children's Hospital - Nedlands
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Recruitment hospital [13]
18524
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Royal Hobart Hospital - Hobart
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Recruitment postcode(s) [1]
18687
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2031 - Randwick
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Recruitment postcode(s) [2]
25754
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2050 - Camperdown
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Recruitment postcode(s) [3]
18688
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2145 - Westmead
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Recruitment postcode(s) [4]
18690
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2305 - New Lambton
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Recruitment postcode(s) [5]
25753
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3000 - Melbourne
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Recruitment postcode(s) [6]
18685
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3052 - Parkville
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Recruitment postcode(s) [7]
25749
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3168 - Clayton
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Recruitment postcode(s) [8]
25752
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4101 - South Brisbane
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Recruitment postcode(s) [9]
25751
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4102 - Woolloongabba
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Recruitment postcode(s) [10]
25750
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5000 - Adelaide
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Recruitment postcode(s) [11]
18689
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5006 - North Adelaide
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Recruitment postcode(s) [12]
32862
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6009 - Nedlands
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Recruitment postcode(s) [13]
32863
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7000 - Hobart
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Recruitment outside Australia
Country [1]
21290
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New Zealand
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State/province [1]
21290
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Auckland, Christchurch
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Country [2]
24667
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United States of America
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State/province [2]
24667
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North Carolina
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Funding & Sponsors
Funding source category [1]
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Government body
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Name [1]
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NHMRC
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Address [1]
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16 Marcus Clarke St,
Canberra City,
ACT 2600
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Country [1]
298490
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Australia
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Primary sponsor type
Other Collaborative groups
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Name
Australian and New Zealand Children’s Haematology and Oncology Group (ANZCHOG)
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Address
27-31 Wright Street, Clayton VIC 3168
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
297633
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Country [1]
297633
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Sydney Children’s Hospitals Network Human Research Ethics Committee
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Ethics committee address [1]
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Corner Hawkesbury Road and Hainsworth Street Locked Bag 4001 Westmead NSW 2145 Sydney Australia DX 8213 Parramatta
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Ethics committee country [1]
299477
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Australia
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Date submitted for ethics approval [1]
299477
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10/10/2017
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Approval date [1]
299477
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22/01/2018
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Ethics approval number [1]
299477
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HREC/17/SCHN/425
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Ethics committee name [2]
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Central Health and Disability Ethics Committee
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Ethics committee address [2]
302705
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Ministry of Health 133 Molesworth Street PO Box 5013 Wellington 6011
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Ethics committee country [2]
302705
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New Zealand
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Date submitted for ethics approval [2]
302705
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05/07/2018
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Approval date [2]
302705
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28/08/2018
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Ethics approval number [2]
302705
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18/CEN/129
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Summary
Brief summary
This a multicentre phase II clinical trial to establish if low dose continuous Panobinostat is effective and safe in patients with relapsed or refractory cancer. Who is it for? You may be eligible for this study if you are less than 40 years old and have relapsed or refractory osteosarcoma, rhabdoid tumour and/or neuroblastoma. Study details All participants will receive oral Panobinostat for up to 12 months after completing their conventional therapy. Participants will have physical examinations, blood tests, urine tests, ECGs and imaging, including MRI/CT, MIBG or FDG-PET (depending on tumour type). This study will test the effectiveness of this new drug in paediatric, adolescent and young adult patients in cases where treatment options are limited.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Jayesh Desai
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Address
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Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, VIC, 3000
AUSTRALIA
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Country
80542
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Australia
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Phone
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+613 8559 7379
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Fax
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Email
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Jayesh.Desai@petermac.org
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Contact person for public queries
Name
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Robyn Strong
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Address
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ANZCHOG
Hudson Institute of Medical Research
27-31 Wright St, Clayton 3168
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Country
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Australia
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Phone
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+613 8572 2684
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Fax
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+613 9902 4810
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Email
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robyn.strong@hudson.org.au
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Contact person for scientific queries
Name
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Jayesh Desai
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Address
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Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, VIC, 3000
AUSTRALIA
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Country
80544
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Australia
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Phone
80544
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+61 3 8559 7379
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Fax
80544
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Email
80544
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Jayesh.Desai@petermac.org
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Aggregate results will be made available publicly
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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
Source
Title
Year of Publication
DOI
Dimensions AI
Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy
2021
https://doi.org/10.3390/cancers13205145
N.B. These documents automatically identified may not have been verified by the study sponsor.
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