Childhood Brain Tumor, Childhood Cancer, Childhood Leukemia, Childhood Solid Tumor, Refractory Cancer, Relapsed Cancer
Conditions
Keywords
children, precision medicine, personalised medicine, molecular profiling, pediatric, paediatric
Brief summary
To improve outcomes for childhood cancer patients through the implementation of precision medicine.
Detailed description
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.
Interventions
GENETICWhole Genome Sequencing
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.
GENETICRNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
GENETICDNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
GENETICTargeted Panel Sequencing
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
GENETICHigh Throughput Sequencing (in vitro)
High throughput drug screening will be attempted for tumors from Cohort 1 (high-risk cancers with survival \<30%) and selected tumor types.
GENETICPatient Derived Xenograft (PDX)(in vivo)
In vivo drug testing in patient derived xenograft (PDX) will be attempted for tumors from Cohort 1 (high-risk cancers) and selected tumor types.
OTHERLiquid Biopsy
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.
Sponsors
Children's Cancer Institute (CCI)
Minderoo Foundation
Medical Research Future Fund
Australian & New Zealand Children's Haematology/Oncology Group
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
0 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Age \< 18 years Note: Individual patients aged 19 - 25 years old with a pediatric cancer, e.g., neuroblastoma, may be enrolled after discussion with, and at the discretion of, the Study Chair or their delegate. 2. Life expectancy \>6 weeks at time of enrolment 3. Consent i. Signed and dated informed consent for study enrolment from participant aged ≥ 18 years or from parent/guardian of participant aged \<18 years. ii. Separate signed and dated informed consent for understanding the role of germline testing and choice for the return of germline results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Utility of recommended personalized therapy for HR childhood cancer patients. | 5 years | 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 |
| Utility of recommended personalized therapy for non-HR childhood cancer patients. | 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Utility of Molecular Tumour Board (MTB) recommendation tier system for HR childhood cancer patients. | 5 years | 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. |
| Utility of preclinical testing in HR childhood cancer patients. | 5 years | 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 |
| Utility of pre-defined virtual molecular panel for non-HR childhood cancer patients. | 5 years | 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. |
| Treatment outcome in HR childhood cancer patients who have received recommended personalised therapy which are molecularly and/or preclinically directed. | 5 years | 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) |
| Clinical utility of germline WGS in patients with childhood cancers. | 5 years | 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 |
| Utility of comprehensive precision medicine for patients with rare tumors in childhood. | 5 years | 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. |
Countries
Australia, New Zealand
Contacts
Primary ContactNational Study Coordinator
Outcome results
None listed