Patients with suspected or confirmed renal cell carcinoma who have consented will either donate tissue, or complete a structured questionnaire or a semi-structured interview. Not all patients will have all three interventions, each patient must have at least one.

Subjects will be asked to complete either structured questionnaires, semi-structured interviews or donate tissue. There will be some overlap, but each subject does not have to do all three interventions.

Questionnaires, interviews and or tissue donation

Mark Emberton

In England, more than three hundred thousand people are diagnosed with cancer each year. The diagnostic and treatment pathways for multiple cancers have greatly developed over the past decade. However, novel treatments are expensive and currently discrimination between responders and non-responders is still suboptimal. There is a pressing need to develop tools that allow for better disease characterisation and stratification. Personalised medicine, whereby prevention, diagnosis, and treatment of diseases is aimed at the individual level, is a growing field. Predicting patient-specific treatment response is challenging as response depends not only on the characteristics of cancer cells but also on how these cells interact with their immediate surrounding environment and on how the tumour interacts with the host. A simplistic model is therefore insufficient to predict treatment response. Complex, patient-derived animal models have been used to this effect but are expensive, may take up to 6 months to provide clinically relevant answers, and pose ethical issues. In the past in vitro models lacked complexity as they were based solely on the two-dimensional (2D) growth of cancer cells. Nowadays the use of 3D tumour models has provided an extra level of complexity to in vitro studies. With these models it is possible to recreate tumour characteristics that were lost in 2D, such as cell-cell interaction between cancer cells and between cancer and stromal cells, cell-matrix interaction, or hypoxia.

The investigators have developed a 3D complex tumour model - named tumouroid. Using this model, preliminary work has been undertaken which allows the growth of patient-derived tumouroids using primary cancer cells from patients.

This personalised platform can be challenged by therapeutics used in clinical practice and response to treatment can be assessed via appropriate assays.

The study goals are twofold:

To assess patient acceptability to the use of patient derived tumour models for future decision-making, and To assess the feasibility of generating patient derived renal cancer tumouroids and using them as platforms to test drug response.

This trial is a prospective tissue collection of renal cell carcinoma samples, including collection of data using both structured Likert 12 item questionnaires and semi structured interviews to assess acceptability. With the development of patient-derived tumouroids the investigators would like to overcome the current over-simplified strategies that focus on genetic markers as predictors of response. In the future, the investigators hope to establish tumouroids as a personalised platform to predict patient response to treatment that is more cost-efficient and poses less ethical issues than animal platforms.

This project will assess if patient-derived tumouroids can be therapeutically challenged and if patients would be willing to accept that such platform to guide clinical treatment decision making.

This study is designed to assess primarily patient acceptability. Acceptability will be elicited using Likert scale non-validated questionnaires and in a semi-structured interview in which the views and preferences relating the acceptability or otherwise of the patient derived tumour models and their impact on future decision making will be explored.

The study will also assess feasibility of building tumouroids and challenging them. Feasibility will address the successful transition between the critical phases of generating a viable and responsive tumour model. This begins with the extraction of cancer cells from the explanted tumour and ends with the determination of a response or otherwise to a therapeutic challenge of the viable tumour model at a range of in vitro concentrations.

The findings of this study will be presented at conference(s) and manuscripts will be submitted to appropriate journals for publication.

Acceptability and Feasibility Study of Patient-specific 'Tumouroids' as Personalised Treatment Screening Tools

A Single Site Study Accessing the Acceptability and Feasibility of Patient-specific 'Tumouroids' as Personalised Treatment Screening Tools

Measured using a Likert scale non-validated structured questionnaire and/or complete a semi structured interview.

Number of tumour tissue samples that can be collected within the time frame from consented patients this will be counted.

Each sample obtained will be weighed and measured.

A physical count of the number of cells isolated from each sample will be collected.

Measurements will be taken of each tumouroid as it grows, each tumouroid will be given ten days to grow at day ten drug challenge will begin..

A log will be kept of the drug concentrations used on all tumouroids.

Number of days tumouroid was exposed to drug

At the end of 5 days of drug exposure tumouroids will be assessed for response to the drug using a commercially available kit that assesses cell metabolism and viability. In addition, tumouroids will be fixed so that cell morphology will be assessed within 6 days of the end of drug exposure.

University College, London

Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Nervous System Diseases

Rare Diseases

Recurrence

Leukemia

Brain Neoplasms

Brain Tumor, Childhood

1. Laboratory analysis including:

   A. Tumour molecular profiling: targeted whole exon variant analysis, whole genome (DNA) and transcriptome (RNA) sequencing, methylation analysis, proteomics analysis, immunohistochemistry B. In vitro high-throughput drug sensitivity testing C. In vivo drug testing using patient-derived xenograft (PDX) models D. Liquid biopsies
2. Multi-disciplinary Tumour Board case discussion
3. Recommendation of personalised therapy

Molecular profiling and drug testing

A/Prof David Ziegler, MBBS

This is a multicentre prospective study of the feasibility and clinical value of a diagnostic service for identifying therapeutic targets and recommending personalised treatment for children and adolescents with high-risk cancer.

This is a multicentre study conducted under the Zero Childhood Cancer Program. The study will be enrolling patients under the age of 21 with high-risk cancer over 3 years from cancer centres in Australia. Patient's cancer cells will be tested for genetic abnormalities (mutations) and undergoing drug testing in highly specialised laboratories. A Multidisciplinary Tumour Board comprising of oncologists, clinical geneticists and scientists will then discuss the results of each case and determine whether a personalised medicine recommendation can be made. A report describing the results and Tumour Board recommendation (if any) will be provided to the patient's treating doctor. It is always at the discretion of the treating doctor whether to alter the patient's management based on the information arising from this research project.

Fresh, cryopreserved or frozen tumor, bone marrow or blood

PRecISion Medicine for Children With Cancer

A Multicenter Prospective Study of the Feasibility and Clinical Value of a Diagnostic Service for Identifying Therapeutic Targets and Recommending Personalised Treatment for Children and Adolescents With High-risk Cancer

Time interval from enrollment until disease progression or death for patients who have received personalized therapy versus those who have not

Time interval from enrollment until death for patients who have received personalized therapy versus those who have not

Proportion of patients for whom personalized medicine recommendation can be made using a comprehensive diagnostic platform within a clinically relevant timeframe

Proportion of tumor samples found to have actionable molecular alterations

Proportion of tumours where in vitro high throughput drug screening and in vivo drug sensitivity testing can be successfully performed

Proportion of tumors for which a potential treatment option is identified by in vitro or in vivo drug screening

Number of weeks from enrollment to issuing a report to the treating clinician

Proportion of patients who subsequently receive the recommended personalized therapy

Description of the barriers or reasons for patients not receiving the recommended personalized therapy

Children's Cancer Institute Australia

Australian & New Zealand Children's Haematology/Oncology Group

Garvan Institute of Medical Research

German Cancer Research Center

Sydney Children's Hospitals Network

Professor

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)

Children's Cancer Institute (CCI)

Minderoo Foundation

Medical Research Future Fund

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Carcinoma

Prostatic Neoplasms

Carcinoma, Renal Cell

Carcinoma, Transitional Cell

Testicular Neoplasms

Kidney Neoplasms

Penile Neoplasms

Urologic Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Genital Neoplasms, Male

Genital Diseases

Genital Diseases, Male

Endocrine Gland Neoplasms

Endocrine System Diseases

Testicular Diseases

Gonadal Disorders

Penile Diseases

Renal Cell Carcinoma

Transitional Cell Carcinoma

Penile Cancer

This is a prospective "n-of-1" type of trial where every patient is his/her own control. This is a study further developing the translational use of an existing framework and infrastructure for systematic sample collection an analytics previously established in the HUB project incorporating NGS and DSRT into clinical care.

Personalised treatment

Antti S Rannikko, MD, PhD

Antti s Rannikko, MD, PhD

Östling Päivi, PhD

Tuomas Mirtti, PhD

Petri Bono, PhD

Harry Nisen, PhD

Katriina Peltola, PhD

Olli Kallioniemi, PhD

Jukka Sairanen, PhD

Petrus Järvinen, PhD

Henrikki Santti, PhD

Anssi Petas, PhD

Mika Matikainen, PhD

Riikka Järvinen, PhD

Hanna Vasarainen, PhD

Tuomas Kilpeläinen, PhD

Mauri Kouri, PhD

Tapio Utriainen, PhD

Kimmo Taari, PhD

Vesa Rahkama, MSc

Andrew Erickson, MSc

Saeed Khalid, MSc

Maija Puhka, PhD

Vilja Pietiäinen, PhD

Lassi Paavolainen, MSc

Dmitry Bykhov, MSc

Teijo Pellinen, PhD

Sami Blom, MSc

Taija af Hällström, PhD

Kevin Sandeman, MD

Anu Kenttämies, PhD

Outi Oksanen, MD

Jarkko Pajarinen, PhD

Jari Siironen, PhD

The purpose of the study is to evaluate whether state-of-the-art technologies such and next generation sequencing and drug sensitivity and resistance testing of patient derived tumour tissue can facilitate research translation and improve outcome of urologic cancers.

Access to high-quality clinical patient material (e.g. tissue of primary tumor and metastasis, plasma and urine) linked to comprehensive registry and clinical data and molecular characterization of the patient material using state-of-the-art technologies (e.g. NGS, transcriptomics, imaging, DSRT) will facilitate a more rapid translation of basic research innovations into clinical care (diagnostics, imaging, therapeutics) and result in improved outcome of patients suffering from urologic cancers ("personalized medicine").

The principal aim of the project is to establish a framework and infrastructure for the systematic collection and interpretation of biological patient samples. Similarly, the investigators aim to establish the format how the related clinical and research data can be made readily accessible for both clinicians and researchers without compromising patient privacy. The key objectives of the project are to facilitate research translation and to improve outcome of urologic cancers.

Development of Diagnostics and Treatment of Urological Cancers

The magnitude of successful clinical translation is measured by the number of times project-derived personalized medicine has impacted patients care by application of novel and existing biomarkers and therapies (e.g. sequencing, DSRT) by 2020

Successful pre-clinical translation, the magnitude of which is measured by the number of times project-derived potential druggable targets or able to re-purpose treatment options were identified within the project by 2020.

Translation of preclinical data into clinically useful data. The success of which is measured by the number of times preclinical data (e.g. sequencing, DSRT) was transformed into clinically useful form within 4 weeks from the time the initial sampling of the specimen was done.

Representativeness is based on the genetics of the cell model and the parental tumor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Acceptability and Feasibility Study of Patient-specific 'Tumouroids' as Personalised Treatment Screening Tools	NCT03300102	Cancer	Questionnaires,...	18 Years -	University College, London
PRecISion Medicine for Children With Cancer	NCT03336931	Childhood Cance... Childhood Solid... Childhood Brain... Childhood Leuke... Refractory Canc... Relapsed Cancer	Molecular profi...	- 21 Years	Sydney Children's Hospitals Network
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
Development of Diagnostics and Treatment of Urological Cancers	NCT02994758	Prostate Carcin... Kidney Cancer Urothelial Carc... Testicular Canc... Penile Cancer	Personalised tr...	18 Years -	Helsinki University Central Hospital
Personalized Medicine for Advanced Biliary Cancer Patients	NCT05615818	Biliary Tract N...	Futibatinib Ivosidenib Zanidatamab Trastuzumab Neratinib Encorafenib Binimetinib Niraparib Cisplatin Gemcitabine	18 Years -	UNICANCER
Feasibility of a Molecular Characterisation Approach to Treatment	NCT02112357	Advanced Gastro...		18 Years -	Royal Marsden NHS Foundation Trust
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
Feasibility of a Molecular Characterisation Approach to Treatment	NCT02112357	Advanced Gastro...		18 Years -	Royal Marsden NHS Foundation Trust
Development of Diagnostics and Treatment of Urological Cancers	NCT02994758	Prostate Carcin... Kidney Cancer Urothelial Carc... Testicular Canc... Penile Cancer	Personalised tr...	18 Years -	Helsinki University Central Hospital

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