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           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         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