Neoplasms

Blood and Lymph Conditions

All Conditions

Nervous System Diseases

Rare Diseases

Leukemia

Brain Neoplasms

Brain Tumor, Childhood

Hematinics

All Drugs and Chemicals

Anti-Infective Agents

Liver Extracts

Formaldehyde

One of the following two criteria must be met:

1. Confirmed or suspected high-risk malignancy defined as expected overall survival \< 30% based on current literature for the specific cancer
2. Cancers for which standard therapy would result in unacceptable and severe morbidity (e.g., infantile fibrosarcoma where definitive surgery would require amputation of limb) Note: This does not include HR neuroblastoma at diagnosis as this group of patients have an overall survival ≥30% and belongs to Cohort 4A.

At least one of the following three criteria must be met:

1. A rare tumor of uncertain prognosis due to rarity of disease
2. A rare tumor with no established treatment strategy
3. A cancer where routine histopathological examination has not been able to establish a diagnosis
4. Confirmed histiocytic disorder AND molecular profiling may facilitate diagnosis and/or treatment
5. Confirmed proliferative vascular or lymphatic malformation AND has failed conventional treatment, e.g., surgery or embolization, OR no appropriate treatment is available AND the disease is organ, limb or life threatening, or debilitating

Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors

Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma

Patient is confirmed by flow cytometry to have acute myeloid leukemia (AML) or other leukemias (Note: Verbal confirmation of flow cytometry result is adequate for enrolment)

Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment)

Patient is suspected or confirmed to have a lymphoma

Patient is suspected or confirmed to have a sarcoma Includes gastrointestinal stromal tumour (GIST), malignant peripheral nerve sheath tumour (MPNST), desmoplastic small round cell tumour (DSRCT)

Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney

Patient is suspected or confirmed to have a liver or biliary tree tumor

Patient is suspected or confirmed to have a thyroid or endocrine cancer

Patient is suspected or confirmed to have a tumor which does not fit into any of the above

One of the following two criteria must be met:

1. Patients whose submitted tumor sample could not yield sufficient DNA for any molecular analysis AND participants/parents have consented to return of germline findings.
2. Patients who do not have appropriate tumor sample to be submitted for molecular profiling may be considered for germline only analysis. Obtaining tumor samples wherever possible will be encouraged.

Each tumor sample will be sequenced and analyzed in parallel with its matched normal (germline DNA from the same patient) to enable the identification of somatic aberrations.

Whole Genome Sequencing

Results will be used for bioinformatics analysis for fusion transcripts and gene expression.

RNA seq

Genome-wide assessment of DNA methylation will be conducted on all samples where possible.

DNA Methylation

Targeted panel sequencing may be performed:

1. When WGS is not feasible or appropriate, e.g., insufficient DNA from fresh or frozen sample or only Formalin-Fixed Paraffin-Embedded (FFPE) material is available
2. When mosaicism is suspected
3. When indicated for a disease type

Targeted Panel Sequencing

High throughput drug screening will be attempted for tumors from Cohort 1 (high-risk cancers with survival \<30%) and selected tumor types.

High Throughput Sequencing (in vitro)

In vivo drug testing in patient derived xenograft (PDX) will be attempted for tumors from Cohort 1 (high-risk cancers) and selected tumor types.

Patient Derived Xenograft (PDX)(in vivo)

Liquid biopsy will be investigated as a non-invasive method for diagnosis of tumors that are difficult to biopsy directly, understanding tumor heterogeneity, monitoring of treatment response, and detection of minimal residual disease (MRD)/relapse in leukemia, solid and CNS tumors.

Liquid Biopsy

National Study Coordinator

Suzanne Milne

Natasha Brown

David Nolan

Amanda St John

Karli Williamson

Rebecca Jensen

Jennifer McConnell

Sandra Montez

Anthea Ng

David Ziegler

To improve outcomes for childhood cancer patients through the implementation of precision medicine.

Through the pilot TARGET and national PRISM trials the feasibility and benefits of using comprehensive molecular profiling and preclinical drug testing in real time for high-risk (HR) patients has been demonstrated. However, the role of precision medicine, especially in facilitating diagnosis and risk stratification in non-HR childhood cancers has not been studied. Integrative tumor-germline whole genome sequencing (WGS) analysis has the potential to advance our understanding of cancer predisposition. In this study, the ZERO platform will be extended to all children with cancer in Australia and New Zealand, evaluating the benefits of precision medicine in different childhood cancer types and risk groups.

Tumour, blood, bone marrow, cerebrospinal fluid (CSF), urine, skin biopsy, cytogenetic culture, extracted DNA and peripheral blood stem cells.

Precision Medicine for Every Child With Cancer

Disease control rate (stable disease + partial response + complete response) in HR patients who have received recommended personalized therapy which are molecularly and/or preclinically directed

The proportion of non-HR patients for whom the disease specific, clinically relevant, virtual molecular panel provides additional or equivalent results for diagnosis and risk stratification when compared with routine diagnostic tests.

The proportion of non-HR patients for whom a pre-defined virtual molecular panel; leads to a streamline molecular report issued within 4 weeks from receipt of samples, changes or refines the initial histopathological diagnosis, changes or refines risk stratification at diagnosis, changes or refines treatment at diagnosis and/or facilitates enrolment in clinical trials requiring prior molecular studies.

Proportion of rare cancer cohort patients for which comprehensive precision medicine improves diagnosis, identifies at least one therapeutic target or facilitates improvement in therapy within a clinically relevant timeframe.

Evaluation of the correlation of MTB recommendation tier to treatment outcome, clinician rated value of MTB recommendation tier in facilitating therapeutic decision and drug access and proportion of HR patients for which the MTB recommendation improves diagnosis, risk stratification or facilitates improvement in therapy within a clinically relevant timeframe.

Evaluation of proportion of tumors where in vitro sensitivity testing can be successfully performed compared with PRISM trial, turnaround time for preclinical in vitro and in vivo drug testing, proportion of tumors where in vitro drug sensitivity identifies additional molecular drivers and proportion of patients for whom preclinical testing:

i. Facilitates therapeutic decision ii. Identifies additional therapeutic options in patients for whom genomic profiling did not identify molecular targets iii. Predicts clinical outcome

Evaluation of;

1. Proportion of HR and non-HR patients with a reportable germline finding (i. For whom the result was not previously known ii. For whom the results would have been missed using current clinical testing criteria)
2. Proportion of patients for whom medical management for the current cancer and future cancer risk has been altered based on the germline findings

Evaluation of;

1. Objective response in patients who have received single agent versus combination personalized therapy
2. Disease control (stable disease + partial response + complete response) in patients who have received a single agent versus combination personalized therapy
3. Progression-free interval (PFI) ratio: PFI personalized therapy : PFI conventional therapy
4. Difference in outcome between patients have received recommended personalised therapy and those who did not (i. Proportion of patients without progression or death at 6 and 12 months between the two groups ii. Difference in progression-free and overall survival between the two groups)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Precision Medicine for Every Child With Cancer	NCT05504772	Childhood Cance... Childhood Solid... Childhood Brain... Childhood Leuke... Refractory Canc... Relapsed Cancer	Whole Genome Se... RNA seq DNA Methylation Targeted Panel ... High Throughput... Patient Derived... Liquid Biopsy	0 Years - 25 Years	Australian & New Zealand Children's Haematology/Oncology Group
Precision Medicine for Every Child With Cancer	NCT05504772	Childhood Cance... Childhood Solid... Childhood Brain... Childhood Leuke... Refractory Canc... Relapsed Cancer	Whole Genome Se... RNA seq DNA Methylation Targeted Panel ... High Throughput... Patient Derived... Liquid Biopsy	0 Years - 25 Years	Australian & New Zealand Children's Haematology/Oncology Group

Spots Global Cancer Trial Database for targeted panel sequencing