PAEDIATRIC ONCOLOGY AND CLINICAL RESEARCH AT THE CHILDREN’S CANCER CENTRE

PAEDIATRIC ONCOLOGY AND
CLINICAL RESEARCH AT THE
CHILDREN’S CANCER CENTRE
MONASH CHILDREN’S (MMC)
Dr. Peter Downie FRACP
Head, CCC Monash Children’s
Paediatric Cancer in Context

There are approximately 200 children diagnosed
with cancer in Victoria each year
 Approximately
45% - leukaemia + lymphoma
 25% CNS tumours


Likelihood of diagnosis of cancer from birth to
adulthood 1:300 males/1:333 females
More common in industrialised nations
Incidence of Cancer in Children under 15 years in Selected
areas of the World
Fiji Indian
India
Fiji Fijian
Israel Non-Jews
Israel Jews
USA
Spain
Australia
Sweden
New Zealand
Brazil
Nigeria
0
100
200
Rate/million
Distribution of Cancers in Children
under 15 years
Leukaemia
35%
Lymphoma 14%
Neuroblastoma
9%
Other 5%
Liver 1%
Retinoblastoma
3%
Bone and STS 15%
Wilms' 8%
CNS 20%
Health of Australian Children


ABS data – approximately 4.5
million children aged under 15
years in Australia or 20% of the
total population
Health gains




better living conditions
education
medical care and vaccination ~
would suggest that this generation
of children should be the healthiest
ever
Emerging concerns related to
rapid social change and
associated new morbidities such as
increasing levels of behavioural,
developmental, mental health and
social problems


In 2006, 41% of children aged
under 15 years had a long-term
health condition compared with 44%
in 2001(ABS 2006 & ABS 2002).
Boys (44%) were more likely than
girls (38%) to have a long term
health condition.


Respiratory diseases - 20% of
children - the main conditions were
asthma (12%), hayfever and allergic
rhinitis (8%) and chronic sinusitis (3%)
Mental and behavioural problems
were reported for 7% of children
overall - these main conditions were
behavioural & emotional problems
with usual onset in childhood or
adolescence (3%) and problems of
psychological development (3%)
Australian Childhood mortality


In a single year (2004) there were 569 deaths of
children aged 1-14 years. The death rate for
children was 15 per 100,000 children (ABS 2006c).
Of the total deaths of children aged 1-14 years,
60% were male and 40% were female resulting in
death rates of 18 per 100,000 boys and 13 per
100,000 girls.
Australian Childhood mortality


Assault accounted for 9% of childhood deaths
between 1999 and 2003 (128 childhood deaths).
Of these deaths, two thirds (65%) occurred for
children aged under five years (ABS 2005a).
The major causes of death in children were;
 external
causes (36%)
 cancer (19%)
 diseases of the nervous system (11%)
 External
causes of death among children – traffic accidents,
accidents at home, accidental drowning. (ABS 2006)
Australian childhood mortality
The major causes of death in children were from ~
external causes (36%): cancer (19%): and diseases of the nervous system (11%)
(ABS 2006 publication)
Causes of Death in Children aged 1-14 2006
Accidents Total 44%
Cancer 19%
Congenital anomalies
8.4%
Heart disease 4%
Pneumonia and flu 1.8%
Cerebral palsy 1.5%
Meningitis 1.1%
Other 16%
Comparison Charts; USA Populations 2010
Cause of death children and adolescents 0-19 years


A: Children 0-14 yrs
B: Adolescents 15-19
years
Monash Children’s Cancer Centre
MMC CCC new patient referrals
Children's Cancer Centre - new patient numbers/year
60
55
52
50
44
40
40
35
30
24
20
10
10
0
52
MMC CCC outpatient attendances
Children's Cancer Centre - Medical OP Clinic Numbers
3000
2500
2000
1500
1000
500
0
2002-03 2003-04 2004-05 2005-06 2006-07 2007-08 2008-09 2009-10 2010-11 2011-12 2012-13
Children's Cancer Centre - Medical OP Clinic Numbers
MMC CCC IP data
Paediatric Oncology/Haematology Inpatient Data
4500
4000
3956
3538
3500
3000
2981
Separations
2500
2000
1500
1985
1317
1038
1000
500
0
678
625
1183
689
1359
820
1287
840
LOS
1331
1138
1463
1504
Childhood cancer distribution
Diagnosis since 07/11/2011
Disease
ALL
AML
CML
Hodgkins
NHL; other Lymphoma and
Burkitt’s
Wilms
Number
32
2
2
12
Rhabdomyosarcoma (abdominal/myxoid)
Neuroblastoma
Aplastic anemia
Pilocytic Astro
Medulloblastoma
Ependymoma
Pontine/PNET
Ewings
Pineoblastoma
Rhabdoid
Immature Teratoma
Osteosarcoma
Granulosa Cell
8
5
3
3
3
2
2
2
1
1
1
1
1
95
8
6
Bone
Wilms'
Neuroblastoma
Lymphomas
Brain
Leukaemias
0
10
20
Percent of new cases
30
40
Children’s Cancer Centre MMC

Increasing patient referrals and complexity of care
Collaboration with other sites around Australia and
New Zealand
ANZCHOG – main office in the MiMR
ACCT

Membership of COG



Impact of clinical trials
CHILDREN’S CANCER CENTRE

Current clinical trials open for disease groups






Acute lymphoblastic leukaemia
Relapsed ALL
Infant leukaemia
Rhabdomyosarcoma – limited
Ependymoma (phase II) chemotherapy/second surgery/reduced field
radiation
Trials in process of opening





Neuroblastoma (COG)
DIPG (COG)
Ewing’s (ASSG)
Medulloblastoma (COG)
NHL – (COG and I-BFM)
Clinical trials at Monash CCC
Current open studies
Open studies at MCCC
AALL 08B1
AALL 03B1
AALL 0232
AALL 0434
AALL 0932
AALL 1131
AALL 0331
AAML 08B1
AREN 03B2
D9902
UK R3
Interfant-06
Closed studies
ACNS 0121
ADVL 0821
AREN 0321
ARST 0331
ARST 0332
LBH 589
Enrolled (on/off) study
patients
16
25
7
6
8
0
11
0
1
1
3
0
2
0
0
0
0
1
Patient diagnoses
Diagnoses since 07/11/2011
ALL
Hodgkins disease
NHL/Lymphoma
Wilms
Rhabdomyosarcoma (botryoidal/embryonal)
Neuroblastoma
Aplastic anemia
Pilocytic Astrocytoma
AML
Medulloblastoma
Ependymoma
Burkitt's
CML
Pontine/PNET
Ewings
Pineoblastoma
Rhabdoid tumour
Immature Teratoma
Osteosarcoma
Granulosa Cell ovarian tumour
TOTAL
32
12
6
6
8
5
3
3
2
3
2
2
2
2
2
1
1
1
1
1
95
Monash Children’s Cancer Centre – new
diagnoses
Diagnosis since 07/11/2011
ALL
Hodgkins
NHL/Lymphoma
Wilms
Rhabdomyosarcoma (botryoidal/embryonal/myxoid)
Neuroblastoma
Aplastic anemia **
Pilocytic Astrocytoma
AML
Medulloblastoma
Ependymoma
Burkitt's
CML
Pontine/PNET
Ewings
Pineoblastoma
Rhabdoid tumour of childhood (non-ATRT)
Immature Teratoma
Osteosarcoma
Granulosa Cell ovarian tumour
TOTAL
32
12
6
6
8
5
3
3
2
3
2
2
2
2
2
1
1
1
1
1
95
Children’s Cancer Centre MMC


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AALL08B1 Classification of Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) Active 5/13/2013
AALL08P1 Intensified PEG-Asparaginase in High Risk Acute Lymphoblastic Leukemia (ALL): A Pilot Study
Completed 10/9/2013
AALL0932 Treatment of Patients with Newly Diagnosed Standard Risk B-Lymphoblastic Leukemia (B-ALL) or
Localized B-lineage Lymphoblastic Lymphoma (B-LLy) Active 12/17/2012
AALL1121 A Single-Arm Multicenter Phase II Study preceded by Dose Evaluation to Investigate the
Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent
Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL) Active 4/18/2012
AALL1122 A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib (IND# 66,971) Added to
Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive
(Ph+) Acute Lymphoblastic Leukemia (ALL). Active 11/18/2011
AALL1131 A Phase III Randomized Trial for Newly Diagnosed High Risk B-precursor Acute Lymphoblastic
Leukemia (ALL) Testing Clofarabine (IND# 73789, NSC# 606869) in the Very High Risk Stratum
Active 4/30/2012
AAML0523 A Phase I/II Study of CLOLAR (Clofarabine IND# 73,789) in Combination with Cytarabine in
Pediatric Patients with Refractory/Relapsed Leukemia Completed 8/7/2012
ABTR04B1 Establishing Continuous Cell Lines and xenografts from Pediatric Cancers for Biological and PreClinical Therapeutic Studies Active 10/26/2009
ACCL0631 Impact of Obesity on the Pharmacokinetics of Anticancer Therapy in Children with High Risk
Acute Lymphoblastic Leukemia (ALL) Follow-Up Completed 1/1/2011
ACCL0731 (SCUSF 0402) Glutamic Acid to Decrease Vincristine Toxicity in Children with Cancer Closed to
Accrual 9/20/2012
Children’s Cancer Centre MMC


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AAML08B1 Biology Study of Transient Myeloproliferative Disorder (TMD) in Children with
Down Syndrome (DS) Active 2/23/2009
AAML1031 A Phase III Randomized Trial for Patients with de novo AML using Bortezomib and
Sorafenib (IND#114480; NSC# 681239, NSC# 724772) for Patients with High Allelic Ratio
FLT3/ITD Active 10/21/2013
ABTR04B1 Establishing Continuous Cell Lines and xenografts from Pediatric Cancers for
Biological and Pre-Clinical Therapeutic Studies Active 10/26/2009
ACCL0422 (HLMCC 0201) Adderall-XR vs. Concerta for cancer treatment-related
neurocognitive sequelae and depression in pediatric patients: A randomized phase II study
Follow-Up Completed 3/31/2012
ACCL0933 A Randomized Open-Label Trial of Caspofungin versus Fluconazole to Prevent
Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia
(AML) Active 2/21/2012
ACCL0934 A Randomized Trial of Levofloxacin to Prevent Bacteremia in Children Being
Treated for Acute Leukemia (AL) or Undergoing Hematopoietic Stem Cell Transplantation
(HSCT) Active 2/11/2013
ACCL1034 Impact of Cleansing with Chlorhexidine Gluconate (CHG) on Reducing Central Line
Associated Bloodstream Infection (CLA-BSI) and Acquisition of Multi-Drug Resistant Organisms
(MDRO) in Children with Cancer or Those Receiving Allogeneic Hematopoietic Cell
Transplnation (HCT) Active
ACCRN07 Protocol for the Enrollment on the Official COG Registry, The Childhood Cancer
Research Network (CCRN) Active 1/10/2011
Other research studies
Biobank
PAT study
ALL
17
ALL
7
NBL
3
Hodgkins
2
Hodgkins
2
Medulloblastoma
1
Wilm's
2
Wilms
1
CML
1
Pilomyxoid Astrocytoma
1
Synovial Sarcoma
1
Rhabdomyosarcoma
1
Rhabdomyosarcoma
1
CML
1
Ganglioneuroblastoma
1
NBL
1
Aplastic Anaemia
1
Rhabdoid tumour
1
Immature Teratoma
1
Total
31
15
Clinical Trial Participation Project

Cancer Australia grant deliverable (ANZCHOG)

Specific objectives

Identify factors influencing clinical trial participation
(organisational / system; child / family related issues; staff
related issues)

Examine current processes and systems that facilitate
the adoption of and participation in specific clinical trials

Identify potential future mechanisms to address
identified barriers
Clinical Trial Participation Project

Preliminary work



Key informants interviews
Brief literature review
Data gathering



ACCT service site survey
Retrospective audit of newly diagnosed children
Stakeholder survey
 Paediatric oncologists and related medical staff
 CRAs and other staff
What we learned …..

A total of 319 children were enrolled on a clinical trial in 2010 (this represents
42% of the number of newly diagnosed children in 2010 [n=759])

Trials available per site ranged from 11-64, with an average of 30 trials per site

87/190 children (46%) whose records were reviewed across all sites, were
eligible for a trial available at their ACCT service site

65 / 87 eligible children (75%) were enrolled in a clinical trial with the overall %
of eligible children enrolled on a trial ranging from 25% - 100% per site (ranging
from 1/4 eligible children to 9/9 eligible children per site)

47/65 enrolled children (72%) were children with leukaemia

19/87 eligible children, clinical trial participation was not discussed with their
parents.

Two sites being identified as ‘higher enrollers’, four sites as ‘moderate
enrollers’ and two sites as ‘small sites’.
What we learned….
Key Elements of a Best Practice Program

Organisational culture and clinical leadership

Clinical trial staffing resources and skills



Good range of trials available on site
Streamlined ethics and governance
Optimal internal systems and processes

Clinical trial review and quality improvement processes

National and cross-site collaboration
Key Elements of a Best Practice Program

National and cross-site collaboration

The need to improve outcomes for a gradually
decreasing population of children for whom
outcomes remain poor, often with rare tumours; as a
result it is essential that an even stronger global,
collaborative perspective be undertaken

Increasing pharmaceutical costs and difficulties
accessing drugs
Clinical Trials
 Phase
II testing of candidate agents is (still) the only way
to identify activity of new drugs in “orphan” diseases.
 Molecular arrays - tell us how to match drugs with
tumours ? process will become less empirical.
 E.g. Testing STI-571 (imatinib) in gliomas; drug is an inh
of the bcr-abl kinase activated in CML ~ highly active;
Also an effective inhibitor of related kinase PDGF-R,
overexpressed in many gliomas.
 This - targeted therapy great appeal; but no substitute
for doing comprehensive trials (seen in past with more
“traditional” cytotoxics), as painful and tedious as that
may be.
Clinical trials
We conclude that daunorubicin is
dispensible during induction therapy in
children with good early response to
treatment
-Andre Baruchel, MD
Summary and Challenges




Monash Children’s Cancer Centre currently treats
between 25-30% of Victorian children diagnosed
with malignancies
5th largest in Australia
Ongoing clinical trial activities ~ enrolments
New research initiatives, particularly lab based
 Neuroblastoma
and brain tumour research
 Sustainability
 Collaborations
and partnerships
`