Precision Medicine for Every Child With Cancer (ZERO2)

February 12, 2023 updated by: Australian & New Zealand Children's Haematology/Oncology Group
To improve outcomes for childhood cancer patients through the implementation of precision medicine.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Anticipated)

3500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Adelaide, Australia
        • Not yet recruiting
        • Women's and Children's Hospital
      • Brisbane, Australia
        • Not yet recruiting
        • Queensland Children's Hospital
      • Hobart, Australia
        • Not yet recruiting
        • Royal Hobart Hospital
      • Melbourne, Australia
        • Not yet recruiting
        • Royal Children's Hospital
      • Melbourne, Australia
        • Not yet recruiting
        • Monash Children's Hospital
      • Newcastle, Australia
        • Not yet recruiting
        • John Hunter Children's Hospital
      • Perth, Australia
        • Not yet recruiting
        • Perth Children's Hospital
      • Sydney, Australia
        • Recruiting
        • Sydney Children's Hospital, Randwick
      • Sydney, Australia
        • Not yet recruiting
        • The Children's Hospital at Westmead

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 second to 25 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients <18 years of age with a diagnosis of tumor or cancer Patients aged 19 - 25 years with a diagnosis of a pediatric tumor or cancer

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
High-risk cancers

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.
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Genetic: High 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.
Genetic: Patient 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.
Other: Liquid 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.
Rare tumors

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
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Primary central nervous system (CNS) tumours
Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Neuroblastoma
Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL
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)
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Acute lymphoblastic leukemia (ALL)
Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment)
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Lymphomas
Patient is suspected or confirmed to have a lymphoma
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Sarcomas
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)
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Renal tumors
Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Hepatic and biliary tree tumors
Patient is suspected or confirmed to have a liver or biliary tree tumor
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Thyroid and endocrine tumors
Patient is suspected or confirmed to have a thyroid or endocrine cancer
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Other tumors
Patient is suspected or confirmed to have a tumor which does not fit into any of the above
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.
Germline only

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.
Genetic: Whole 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.
Genetic: RNA seq
Results will be used for bioinformatics analysis for fusion transcripts and gene expression.
Genetic: DNA Methylation
Genome-wide assessment of DNA methylation will be conducted on all samples where possible.
Genetic: Targeted 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
Other: Liquid 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Utility of recommended personalized therapy for HR childhood cancer patients.
Time Frame: 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
5 years
Utility of recommended personalized therapy for non-HR childhood cancer patients.
Time Frame: 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.
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Utility of pre-defined virtual molecular panel for non-HR childhood cancer patients.
Time Frame: 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.
5 years
Utility of comprehensive precision medicine for patients with rare tumors in childhood.
Time Frame: 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.
5 years
Utility of Molecular Tumour Board (MTB) recommendation tier system for HR childhood cancer patients.
Time Frame: 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.
5 years
Utility of preclinical testing in HR childhood cancer patients.
Time Frame: 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
5 years
Clinical utility of germline WGS in patients with childhood cancers.
Time Frame: 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
5 years
Treatment outcome in HR childhood cancer patients who have received recommended personalised therapy which are molecularly and/or preclinically directed.
Time Frame: 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)
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Australian & New Zealand Children's Haematology/Oncology Group

Collaborators

Medical Research Future Fund
Minderoo Foundation
Children's Cancer Institute (CCI)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 16, 2022

Primary Completion (Anticipated)

July 1, 2025

Study Completion (Anticipated)

July 1, 2030

Study Registration Dates

First Submitted

January 30, 2022

First Submitted That Met QC Criteria

August 15, 2022

First Posted (Actual)

August 17, 2022

Study Record Updates

Last Update Posted (Actual)

February 15, 2023

Last Update Submitted That Met QC Criteria

February 12, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • ZERO2

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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