Precision Medicine for Every Child With Cancer
Recruiting
- Conditions
- Childhood Solid TumorChildhood LeukemiaRefractory CancerChildhood CancerChildhood Brain TumorRelapsed Cancer
- Interventions
- Genetic: Whole Genome SequencingGenetic: RNA seqGenetic: DNA MethylationGenetic: Targeted Panel SequencingOther: Liquid BiopsyGenetic: High Throughput Sequencing (in vitro)Genetic: Patient Derived Xenograft (PDX)(in vivo)
- Registration Number
- NCT05504772
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 3500
Inclusion Criteria
- 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.
- Life expectancy >6 weeks at time of enrolment
- 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.
Exclusion Criteria
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description High-risk cancers RNA seq 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. Rare tumors Whole Genome Sequencing 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 High-risk cancers Whole Genome Sequencing 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. Rare tumors RNA seq 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 High-risk cancers DNA Methylation 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. Neuroblastoma RNA seq Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL DNA Methylation 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) Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL Targeted Panel Sequencing 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) Lymphomas Whole Genome Sequencing Patient is suspected or confirmed to have a lymphoma Lymphomas Targeted Panel Sequencing Patient is suspected or confirmed to have a lymphoma Primary central nervous system (CNS) tumours RNA seq Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors High-risk cancers Patient Derived Xenograft (PDX)(in vivo) 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. Neuroblastoma Whole Genome Sequencing Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL Whole Genome Sequencing 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) Lymphomas Liquid Biopsy Patient is suspected or confirmed to have a lymphoma Sarcomas Whole Genome Sequencing 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) Sarcomas RNA seq 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) Renal tumors RNA seq Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney High-risk cancers Targeted Panel Sequencing 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. High-risk cancers High Throughput Sequencing (in vitro) 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. High-risk cancers Liquid Biopsy 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. Rare tumors Targeted Panel Sequencing 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 Primary central nervous system (CNS) tumours Whole Genome Sequencing Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors Primary central nervous system (CNS) tumours DNA Methylation Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL RNA seq 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) Acute myeloid leukemia, myelodysplastic syndrome and other leukemias not classified as ALL Liquid Biopsy 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) Acute lymphoblastic leukemia (ALL) Whole Genome Sequencing Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment) Rare tumors DNA Methylation 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 Rare tumors Liquid Biopsy 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 Primary central nervous system (CNS) tumours Targeted Panel Sequencing Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors Neuroblastoma DNA Methylation Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma Neuroblastoma Targeted Panel Sequencing Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma Acute lymphoblastic leukemia (ALL) RNA seq Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment) Hepatic and biliary tree tumors Targeted Panel Sequencing Patient is suspected or confirmed to have a liver or biliary tree tumor Thyroid and endocrine tumors RNA seq Patient is suspected or confirmed to have a thyroid or endocrine cancer Thyroid and endocrine tumors Liquid Biopsy Patient is suspected or confirmed to have a thyroid or endocrine cancer Other tumors Liquid Biopsy Patient is suspected or confirmed to have a tumor which does not fit into any of the above Germline only RNA seq 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. Primary central nervous system (CNS) tumours Liquid Biopsy Patient is suspected or confirmed to have a primary CNS tumor, including low and high-grade tumors Neuroblastoma Liquid Biopsy Patient is suspected or confirmed to have neuroblastoma 4A: HR neuroblastoma at diagnosis 4B: Non-HR neuroblastoma Acute lymphoblastic leukemia (ALL) Targeted Panel Sequencing Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment) Lymphomas DNA Methylation Patient is suspected or confirmed to have a lymphoma Sarcomas DNA Methylation 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) Renal tumors Whole Genome Sequencing Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney Renal tumors DNA Methylation Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney Hepatic and biliary tree tumors RNA seq Patient is suspected or confirmed to have a liver or biliary tree tumor Hepatic and biliary tree tumors Liquid Biopsy Patient is suspected or confirmed to have a liver or biliary tree tumor Thyroid and endocrine tumors DNA Methylation Patient is suspected or confirmed to have a thyroid or endocrine cancer Thyroid and endocrine tumors Targeted Panel Sequencing Patient is suspected or confirmed to have a thyroid or endocrine cancer Acute lymphoblastic leukemia (ALL) DNA Methylation Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment) Acute lymphoblastic leukemia (ALL) Liquid Biopsy Patient is confirmed to have acute lymphoblastic leukemia by flow cytometry (Note: Verbal confirmation of flow cytometry result is adequate for enrolment) Lymphomas RNA seq Patient is suspected or confirmed to have a lymphoma Sarcomas Targeted Panel Sequencing 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) Renal tumors Targeted Panel Sequencing Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney Thyroid and endocrine tumors Whole Genome Sequencing Patient is suspected or confirmed to have a thyroid or endocrine cancer Other tumors RNA seq Patient is suspected or confirmed to have a tumor which does not fit into any of the above Other tumors DNA Methylation Patient is suspected or confirmed to have a tumor which does not fit into any of the above Germline only Whole Genome Sequencing 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. Sarcomas Liquid Biopsy 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) Renal tumors Liquid Biopsy Patient is suspected or confirmed to have a renal tumor Includes clear cell sarcoma of kidney Hepatic and biliary tree tumors DNA Methylation Patient is suspected or confirmed to have a liver or biliary tree tumor Germline only Liquid Biopsy 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. Hepatic and biliary tree tumors Whole Genome Sequencing Patient is suspected or confirmed to have a liver or biliary tree tumor Other tumors Whole Genome Sequencing Patient is suspected or confirmed to have a tumor which does not fit into any of the above Other tumors Targeted Panel Sequencing Patient is suspected or confirmed to have a tumor which does not fit into any of the above Germline only DNA Methylation 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. Germline only Targeted Panel Sequencing 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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 findingsUtility 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.
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 outcomeUtility 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.
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)
Trial Locations
- Locations (11)
Perth Children's Hospital
🇦🇺Perth, Australia
Women's and Children's Hospital
🇦🇺Adelaide, Australia
Royal Children's Hospital
🇦🇺Melbourne, Australia
John Hunter Children's Hospital
🇦🇺Newcastle, Australia
Starship Children's Hospital
🇳🇿Auckland, Grafton, New Zealand
Queensland Children's Hospital
🇦🇺Brisbane, Australia
Royal Hobart Hospital
🇦🇺Hobart, Australia
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Monash Children's Hospital
🇦🇺Melbourne, Australia
Sydney Children's Hospital, Randwick
🇦🇺Sydney, Australia
The Children's Hospital at Westmead
🇦🇺Sydney, Australia