Trial Review

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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
29/01/2021
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.
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.
Secondary ID [1] 293872 0
ACCT008
Secondary ID [2] 303304 0
ASSG35
Secondary ID [3] 303305 0
CLBH589XAU13T
Universal Trial Number (UTN)
U1111-1208-4010
Trial acronym
NORTH
Linked study record
Phase I study: ACTRN12609000978268

Health condition
Health condition(s) or problem(s) studied:
Osteosarcoma 306338 0
Malignant Rhabdoid Tumour 306339 0
Neuroblastoma 306340 0
Atypical Teratoid/Rhabdoid Tumour (AT/RT) 306723 0
Condition category
Condition code
Cancer 305424 305424 0 0
Children's - Other
Cancer 305929 305929 0 0
Children's - Brain
Cancer 305930 305930 0 0
Bone

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 300152 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304573 0
Efficacy as measured by Clinical Benefit Rate (percentage of patients with stable disease or better using MRI/CT imaging)
Timepoint [1] 304573 0
Every 2 months for 12 months after intervention commencement (primary timepoint is 4 months)
Primary outcome [2] 304577 0
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
Timepoint [2] 304577 0
Weekly for 1 month and then monthly for 12 months after intervention commencement
Secondary outcome [1] 342438 0
Clinical Benefit Rate: Percentage of patients with stable disease or better using functional imaging (MIBG or FDG-PET).
Timepoint [1] 342438 0
Every 2 months for 12 months after treatment commencement
Secondary outcome [2] 342447 0
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.
Timepoint [2] 342447 0
2 years after completion of treatment
Secondary outcome [3] 342448 0
Overall Survival calculated as the time from registration to date of death
Timepoint [3] 342448 0
2 years after completion of treatment

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.
- 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.
- Karnosfsky performance level of > 60% for patients > 10yr of age, OR Lansky performance levels > 60% for patients < 10yr of age.
- Life expectancy of > 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 tested within 1 week of registration
- Adequate renal function tested
- Adequate Liver function
- Adequate cardiac function tested
- Adequate pulmonary function tested.
- Adequate CNS function – seizure free for 2 months prior to study entry
- Adequate serum calcium, magnesium and potassium concentrations tested within 1 week of registration
- 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 guardians have signed a written informed consent form.
Minimum age
No limit
Maximum age
39 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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 >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 > 450msec.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
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.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/04/2018
Actual
9/01/2019
Date of last participant enrolment
Anticipated
1/08/2021
Actual
Date of last data collection
Anticipated
1/08/2023
Actual
Sample size
Target
60
Accrual to date
17
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 9882 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 9884 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 9885 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 9886 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [5] 9887 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [6] 13194 0
Monash Children’s Hospital - Clayton
Recruitment hospital [7] 13195 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 13196 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [9] 13197 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [10] 13198 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [11] 13199 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [12] 18523 0
Perth Children's Hospital - Nedlands
Recruitment hospital [13] 18524 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 18685 0
3052 - Parkville
Recruitment postcode(s) [2] 18687 0
2031 - Randwick
Recruitment postcode(s) [3] 18688 0
2145 - Westmead
Recruitment postcode(s) [4] 18689 0
5006 - North Adelaide
Recruitment postcode(s) [5] 18690 0
2305 - New Lambton
Recruitment postcode(s) [6] 25749 0
3168 - Clayton
Recruitment postcode(s) [7] 25750 0
5000 - Adelaide
Recruitment postcode(s) [8] 25751 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 25752 0
4101 - South Brisbane
Recruitment postcode(s) [10] 25753 0
3000 - Melbourne
Recruitment postcode(s) [11] 25754 0
2050 - Camperdown
Recruitment postcode(s) [12] 32862 0
6009 - Nedlands
Recruitment postcode(s) [13] 32863 0
7000 - Hobart
Recruitment outside Australia
Country [1] 21290 0
New Zealand
State/province [1] 21290 0
Auckland, Christchurch

Funding & Sponsors
Funding source category [1] 298490 0
Government body
Name [1] 298490 0
NHMRC
Address [1] 298490 0
16 Marcus Clarke St,
Canberra City,
ACT 2600
Country [1] 298490 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Children’s Haematology and Oncology Group (ANZCHOG)
Address
27-31 Wright Street, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 297633 0
None
Name [1] 297633 0
Address [1] 297633 0
Country [1] 297633 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299477 0
Sydney Children’s Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 299477 0
Corner Hawkesbury Road and Hainsworth Street
Locked Bag 4001 Westmead NSW 2145 Sydney Australia
DX 8213 Parramatta
Ethics committee country [1] 299477 0
Australia
Date submitted for ethics approval [1] 299477 0
10/10/2017
Approval date [1] 299477 0
22/01/2018
Ethics approval number [1] 299477 0
HREC/17/SCHN/425
Ethics committee name [2] 302705 0
Central Health and Disability Ethics Committee
Ethics committee address [2] 302705 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [2] 302705 0
New Zealand
Date submitted for ethics approval [2] 302705 0
05/07/2018
Approval date [2] 302705 0
28/08/2018
Ethics approval number [2] 302705 0
18/CEN/129

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80542 0
Dr Jayesh Desai
Address 80542 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, VIC, 3000
AUSTRALIA
Country 80542 0
Australia
Phone 80542 0
+613 8559 7379
Fax 80542 0
Email 80542 0
Jayesh.Desai@petermac.org
Contact person for public queries
Name 80543 0
Mrs Robyn Strong
Address 80543 0
ANZCHOG
Hudson Institute of Medical Research
27-31 Wright St, Clayton 3168
Country 80543 0
Australia
Phone 80543 0
+613 8572 2684
Fax 80543 0
+613 9902 4810
Email 80543 0
robyn.strong@hudson.org.au
Contact person for scientific queries
Name 80544 0
Dr Jayesh Desai
Address 80544 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, VIC, 3000
AUSTRALIA
Country 80544 0
Australia
Phone 80544 0
+61 3 8559 7379
Fax 80544 0
Email 80544 0
Jayesh.Desai@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Aggregate results will be made available publicly
What supporting documents are/will be available?
No other documents available
Summary results
No Results