Trial registered on ANZCTR


Trial ID
ACTRN12609000978268
Ethics application status
Approved
Date submitted
4/11/2009
Date registered
12/11/2009
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I Study of LBH589 in Children With Refractory Solid and Central Nervous System (CNS) Tumours
Scientific title
A Phase I Study to determine the Maximum Tolerated Dose (MTD) of LBH589 in Paediatric Patients With Refractory Solid Tumours Including Central Nervous System (CNS) Tumours
Secondary ID [1] 279950 0
Nil
Universal Trial Number (UTN)
Trial acronym

Health condition
Health condition(s) or problem(s) studied:
Relapsed/refractory solid tumours including CNS tumours 252123 0
Condition category
Condition code
Cancer 252327 252327 0 0
Children's - Brain
Cancer 252328 252328 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open label, Phase I, multicentre study evaluating the maximum tolerated dose of LBH589 (Panobinostat) in paediatric patients with refractory solid tumours including CNS tumours.
Patients will be separated into one of two groups depending on age and registered into escalating dose levels.
Group 1: patients < 12 years of age including infants
Group 2: patients >= 12 years - < 18 years
A course of treatment is 3 weeks and LBH589 will be administered intravenously (i.v.) weekly as a 30 min infusion for week 1 and week 2 with week 3 for rest and evaluation. The starting dose is 15mg/m2 and inter-patient dose escalation or reductions will occur, in successive cohorts, at increments of 5mg/m2 with corresponding dose levels of 20mg/m2, 25mg/m2, 30 mg/m2 in cohorts of 3-6 patients until an MTD is reached. Patients may be recruited sequentially to the appropriate age range independent of recruitment to the other age range. Therefore these two recruitment groups will be run in parallel with an independent MTD dosing level being established for each group. Treatment can be continued for up to 17 courses or for up to 12 months.
Intervention code [1] 241503 0
Treatment: drugs
Comparator / control treatment
This study is a dose finding study. Patients will be entered in cohorst of 3 to 6 at varying dose levels.
Control group
Dose comparison

Outcomes
Primary outcome [1] 253191 0
To determine the maximum tolerated dose (MTD) and recommend a Phase II dose of LBH589 for patients in each age group with progressive/recurrent solid tumours including CNS tumours of childhood.
This primary outcome will be assessed for haematologic, biochemical, and cardiac toxicity using blood toxicity analysis and electrocardiogram (ECG).
Timepoint [1] 253191 0
This primary outcome will be assessed during the first course of treatment only which is of 3 weeks duration.
Blood samples and ECGs are taken on Day 1 at pre-dose, immediately prior to end of infusion, 0.25hrs, 1 hr, 3 hr, 6 hr, 24 post infusion and on Day 2 26 - 48 hours post infusion.
ECGs are also taken on Day 8 pre-dose, and Day 9 26 - 48 hours post infusion.
Primary outcome [2] 253192 0
To define and describe the toxicities for patients in each age group of LBH589 administered on this schedule.
This primary outcome will be assesed for haematologic, biochemical, and cardiac toxicity using blood toxicity analysis and ECG.
Timepoint [2] 253192 0
This primary outcome will be assessed over all treatment cycles given with a maximum of 17 cycles or up to 12 months of treatment.
Blood samples and ECGs are taken on Day 1 at pre-dose, immediately prior to end of infusion, 0.25hrs, 1 hr, 3 hr, 6 hr, 24 post infusion and on Day 2 26 - 48 hours post infusion. ECGs are also taken on Day 8 pre-dose, and Day 9 26 - 48 hours post infusion.
During seccond and subsequent cycles blood samples are taken weekly. These should be taken before each infusion if it is Day 1 or Day 8 of the treatment cycle. ECGs are taken pre-dose on Day 1 and Day 9 of the cycle and at days 1, 3, 8 & 10 of the treatment cycle.
Primary outcome [3] 253193 0
To characterise the pharmacokinetics for patients in each age group of LBH589 in children with these refractory cancers.
This primary outcome will be assesed using blood and if available, cerebrospinal fluid (CSF).
Timepoint [3] 253193 0
This primary outcome will be assessed during the first course of treatment only which is of 3 weeks duration.
Blood samples are taken on Day 1 at pre-dose, immediately prior to end of infusion, 0.25hrs, 1 hr, 3 hr, 6 hr, 24 post infusion and on Day 2 26 - 48 hours post infusion.
If CSF samples are to be taken they are taken at the same time as the blood samples.
Secondary outcome [1] 262126 0
To preliminarily define the anti-tumour activity of LBH589 within the confines of a Phase I study.
The anti-tumour activity of LBH589 will be assessed using imaging studies, such as magnetic resonance imaging (MRI) or computerised tomography (CT).
Timepoint [1] 262126 0
This secondary outcome will be assessed via imaging studies undertaken every 3 treatment cycles and then every 3 months following completion of treatment.
Secondary outcome [2] 262127 0
Where possible to assess the biologic activity of LBH589 by measuring histone acetylation status in peripheral mononuclear cells (PMNC), bone marrow and fresh tumour tissue specimens.
Timepoint [2] 262127 0
This secondary outcome is measured during the first course of treatment.
Blood samples are taken on Day 1 at pre-dose, immediately prior to end of infusion, 0.25hrs, 1 hr, 3 hr, 6 hr, 24 post infusion and on Day 2 26 - 48 hours post infusion.
If bone marrow samples are to be taken they will be taken pre-study and at the end of the first course of treatment.
Tumour tissue is only collected if surgery is performed as part of standard of care during the first course of treatment.
Secondary outcome [3] 262128 0
To assess the biologic activity of LBH589 by measuring the effects of the drug on imprinting status and acetylation status in both fresh tumour tissue and peripheral blood mononuclear cells (PBMC) in several target genes including CDKN1C.
Timepoint [3] 262128 0
This secondary outcome is measured during the first course of treatment only.
Blood samples are taken on Day 1 at pre-dose, immediately prior to end of infusion, 0.25hrs, 1 hr, 3 hr, 6 hr, 24 post infusion and on Day 2 26 - 48 hours post infusion.
Tumour tissue is only collected if surgery is performed as part of standard of care during the first course of treatment.

Eligibility
Key inclusion criteria
* Patients must be < 18 years of age.
* Patient must have been histologically diagnosed with refractory solid tumours (including CNS) at time of diagnosis or relapse.
* Patient disease is refractory to conventional therapy or absence of conventional therapy available.
* 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.
* Fully recovered (ie. No evidence of graft versus host disease) from stem cell transplant (SCT).
* Patients with CNS tumours who are receiving dexamethasone are on a stable/decreasing dose for at least 1 week.
* Adequate bone marrow (BM) function tested within 1 week of registration – peripheral blood absolute neutrophil count (ANC) > 1000/ul (or 1 x 109/mL); Platelet > 100 000/ul (or 100 x 109/mL); haemoglobin > 8gm/dL (or >80 g/L).
* Adequate Renal function tested within 1 week of registration – age-adjusted normal serum creatinine or glomerular filtration rate (GFR) >70ml/min/1.73m2.
* Adequate Liver function tested within 1 week of registration – total bilirubin <=1.5 x Institutional Upper Limit of Normal (IULN) for age, serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase(ALT)) <=5 x IULN for age, and albumin >= 2g/dL (20g/L).
* Adequate Cardiac Function tested within 2 weeks of registration – shortening fraction of > 27% by echocardiogram OR ejection fraction of >= 50% by gated radionuclide study
* Adequate Pulmonary function tested within 2 weeks of registration with no evidence of dyspnoea at rest, no exercise intolerance and pulse oximetry (SaO2) >94%
* 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 – all must be >= Institutional Lower Limit of Normal (ILLN) for age with or without supplementation.
* If female and postmenarchal, 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
17 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 (small port) within 2 weeks.
* Have received craniospinal radiotherapy within 3 months.
* Have received >50% radiation of the pelvis within 3 months.
* Have received other substantial BM radiation within 6 weeks.
* Have received allogeneic stem cell transplant within 6 months.
* 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 while on study.
* Are receiving Metronidazole and/or Disulfiram
* Have uncontrolled Sepsis.
* Have previously received LBH589.
* 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)
Patients can be enrolled on the study once all eligibility requirements for the study have been met via the Trial Centre or Study Chair.
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
Other
Other design features
Patients will be separated into one of two groups depending on age and registered into escalating doses. Additional patients in each group will be enrolled depending on the number of toxicities observed. Once the MTD has been determined for each age group, additional patients may be recruited such that a minimum of six patients will be observed at that dosing level. Additional pharmacokinetic data will then be obtained at the MTD dosing level.
Phase
Phase 1
Type of endpoint(s)
Safety

Recruitment
Anticipated date of first participant enrolment
9/11/2009
Actual date of first participant enrolment
24/08/2010
Anticipated date last participant enrolled
Actual date last participant enrolled
30/07/2012
Anticipated date of last data collection
Actual date of last data collection
Target sample size
52
Actual sample size
Recruitment status
Completed
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 243973 0
Commercial sector/Industry
Name [1] 243973 0
Novartis Pharmaceuticals Australia Pty Ltd
Address [1] 243973 0
54 Waterloo Rd
North Ryde NSW 2113
Country [1] 243973 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG)
Address
PO Box 5418 Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 251325 0
None
Name [1] 251325 0
Address [1] 251325 0
Country [1] 251325 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 244083 0
Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 244083 0
Royal Children's Hospital
Flemington Rd
Parkville VIC 3052
Ethics committee country [1] 244083 0
Australia
Date submitted for ethics approval [1] 244083 0
Approval date [1] 244083 0
13/10/2009
Ethics approval number [1] 244083 0

Summary
Brief summary
This is a study examining the use of a new anti-cancer drug called LBH589 in children with solid and central nervous system (CNS) tumours. It is only for children where a tumour does not respond to initial conventional therapies (refractory). At this time there is no standard treatment available for many children who have a refractory solid or CNS tumour. Faulty regulation of a cell protein (enzyme) in the body called a histone deacetylase (HDAC) is known to be present in many human cancers. It changes cell structures and weakens the activity of good cancer killing genes. LBH589 is a new investigational drug that can increase the activity of these good genes by reacting with the HDAC cell protein. It is hoped it will help kill the tumour. Research studies in the laboratory using LBH589 have shown a strong response against tumour cells. In addition LBH589 has shown anti-tumour activity in studies of adult cancer patients. LBH589 is now being investigated in clinical trials of solid and haematological tumours in adults. LBH589 is an investigational or experimental anti-cancer agent that has not yet been approved by either the Food and Drug Administration (FDA) or the Therapeutic Goods Administration (TGA). The drug has however been shown to be safe when given to adults on the schedule that will be used in this study. This study is assessing the dose levels that can be safely tolerated in children with solid and CNS tumours.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30463 0
Prof David Ashley
Address 30463 0
ANZCHOG
27-31 Wright St
Clayton VIC 3168
Country 30463 0
Australia
Phone 30463 0
+613 9902 4852
Fax 30463 0
Email 30463 0
acct@anzchog.org
Contact person for public queries
Name 13710 0
Ms Robyn Strong
Address 13710 0
ANZCHOG
27-31 Wright St
Clayton VIC 3168
Country 13710 0
Australia
Phone 13710 0
+613 9902 4852
Fax 13710 0
+613 9902 4810
Email 13710 0
acct@anzchog.org
Contact person for scientific queries
Name 4638 0
Prof David Ashley
Address 4638 0
ANZCHOG
27-31 Wright St
Clayton VIC 3168
Country 4638 0
Australia
Phone 4638 0
+613 9902 4852
Fax 4638 0
+613 9902 4810
Email 4638 0
acct@anzchog.org