Preventing Viral Pandemic Associated Risk of Cancer Death Using Less Invasive Diagnostic Tests- Liquid Biopsies (PREVAILctDNA)

• ClinicalTrials.gov Identifier: NCT04566614
• Recruitment Status: Recruiting
• First Posted: September 28, 2020
• Last Update Posted: February 22, 2023
• Sponsor: Royal Marsden NHS Foundation Trust
• Information provided by (Responsible Party): Royal Marsden NHS Foundation Trust

Study Description

Brief Summary:

The purpose of this study is to investigate the feasibility of using ctDNA to support cancer diagnosis and risk stratification where invasive aerosol generating testing (and/or tissue biopsy) is challenging due to infection risk, technical impracticalities and resource limitations, such as during the COVID-19 pandemic and the subsequent recovery period.

Condition or disease	Intervention/treatment
Neoplasm, Colorectal; Neoplasm of Lung; Neoplasm, Bladder; Neoplasms Pancreatic; Biliary Tract Neoplasms; Gastro Intestinal Stromal Tumour	Other: ctDNA blood sampling

Detailed Description:

This is a prospective, single-centre cohort pilot study using ctDNA informed treatment decisions. If the pilot study is successful within certain tumour types then this protocol may be extended to investigate further the benefit of ctDNA informed treatment decision in those tumour types.

Patients with suspected malignancy for whom invasive biopsy for definitive histological diagnosis is challenging either due to COVID-19-related resource limitations, infection control or technical feasibility will be considered for this study. In this setting liquid biopsy may be used in lieu of tissue biopsy to facilitate treatment or may be used to prioritise standard of care invasive diagnostic tests. The former includes patients who require repeat biopsies for genomic analysis following non-informative results where these would inform standard of care treatment (i.e. NICE (National Institute for Health and Care Excellence)/Cancer Drug Fund (CDF) approved drugs). Tumour types included in this study are therefore those where invasive aerosol generating diagnostic tests such as bronchoscopy, gastrointestinal endoscopy (including endoscopic ultrasound (EUS)) are part of the standard diagnostic pathway and where capacity for these tests has become severely constrained during (and likely after) the COVID-19 pandemic. Tumour types affected include some suspected biliary tract, bladder, colorectal, GIST, lung and pancreatic cancers.

The study is planned to continue until a total of 144 patients have been enrolled. This is anticipated to take up to 12-18 months. Follow-up will continue until patients have diagnosis made (based on ctDNA result) and treatment decision made (deferred or immediate).

Potential patients will be identified in and will usually at the multidisciplinary team (MDT) meeting. They will give consent to participate in the trial and offered a liquid biopsy (ctDNA) in lieu of a tissue biopsy if considered suitable for PREVAIL - ctDNA. This may include patients who require repeat biopsies for further genomic analyses when repeat biopsies are not feasible where liquid biopsy may support prioritisation for invasive diagnostics earlier. ctDNA analysis will involve copy number variant detection and low coverage whole genomic sequencing. ctDNA gene panels have already been validated against tissue based molecular diagnostics for paediatrics (ct_PAED) and colorectal cancer (ct_GI).

This analysis will be performed in an accredited clinical diagnostic laboratory (Translational Research Laboratory, Institute of Cancer Research). Patients will be stratified for treatment or further investigation based on their ctDNA result (either positive or negative), suspected tumour type, radiological (including PREVAIL-imaging risk stratification pathway) and clinical characteristics.

PREVAIL ctDNA- Part 2 Study:

PREVAIL part 2 is a multi-centre, prospective study assessing the impact of Guardant360© liquid biopsy in patients with radiologically suspicious pancreatic cancer (PC) and biliary tract cancer (BTC)without histological confirmation of malignancy.

Liquid biopsies will be implemented into the routine diagnostic pathway across 6 RMP sites for patients with radiologically suspicious stage III/IV PC/BTC as part of the ACCESS implementation programme. Over 12 months, approximately 650 patients will be identified at individual sites by the local team when seen for an invasive procedure and referred in parallel to the Guardant360© test. These patients will proceed through an invasive diagnostic pathway as is standard of care and have a liquid biopsy as a new standard of care. Most patients will undergo both invasive tissue biopsy and liquid biopsy.

Patients with informative liquid biopsy result, but without a histological diagnosis of cancer (either due to inconclusive biopsy result or if the invasive procedure hasn't been performed) will be considered suitable for the study. Only patients with detectable ctDNA without histological confirmation will be suitable for this study (approximately ¼ of patients entering the ACCESS programme). The study is planned to run parallel to the ACCESS implementation programme and it aims to enrole 150 patients.

As part of this study, treatment may be recommended based on the liquid biopsy result. Patients with an invasive biopsy result which is suitable to guide treatment will not be eligible.

ctDNA results will be discussed at the molecular tumour board (MTB) to provide clinical context and validity of the genomic result. In addition, all patients will be discussed at a central upper gastrointestinal cancer multidisciplinary team meeting (MDM) to discuss treatment based on ctDNA results. Treating clinicians will have access to the MTB outcome and patients may be treated based on the ctDNA result in the context of symptoms, tumour markers, and imaging results as a complete diagnostic package.

Study Design

• Study Type: Observational
• Estimated Enrollment: 294 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Preventing Viral Pandemic Associated Risk of Cancer Death Using Less Invasive Diagnostic Tests- Liquid Biopsies
• Actual Study Start Date: June 18, 2020
• Estimated Primary Completion Date: July 31, 2023
• Estimated Study Completion Date: December 31, 2025

Groups and Cohorts

Group/Cohort	Intervention/treatment
Biliary Tract Cohort; Patients with suspected biliary tract cancer will be offered ctDNA to support a diagnosis in patients with suspected early stage, locally advanced and advanced disease. This includes patients with tumours that are technically challenging to access with invasive biopsy or due to limitations in endoscopic ultrasound due to the COVID-19 pandemic. Patients with histological diagnosis will not be eligible for this study. Patients with suspected cancer will have ctDNA result (positive or negative) discussed at MDT in conjunction with PREVAIL-imaging risk stratification pathway to risk stratify in terms of cancer risk (low, intermediate and high risk), serum tumour markers and patient presentation which will dictate the appropriate treatment. Those with metastatic disease will have their treatment decision based on ctDNA result, radiology and patient characteristics after discussion between the treating clinician and patient	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Bladder Cancer Cohort; Patients with suspected bladder cancer (localised and metastatic) will be offered ctDNA to support their diagnosis, in cases where cystoscopy and biopsy are difficult to obtain due to the COVID-19 pandemic. Patients with histological diagnosis will not be eligible for this study. A positive ctDNA result will be supportive of a diagnosis of bladder cancer, their treatment may be prioritised and decided based on this result in conjunction with radiological findings, patient presentation and after discussion between the treating physician and patient	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Pancreatic Cancer Cohort; Patients with suspected pancreatic cancer will be offered ctDNA to support a diagnosis in patients with suspected early stage, locally advanced and advanced disease. This includes patients with tumours that are technically challenging to access with invasive biopsy or due to limitations in endoscopic ultrasound due to the COVID-19 pandemic. Patients with histological diagnosis will not be eligible for this study. Patients with suspected cancer will have ctDNA result (positive or negative) discussed at MDT in conjunction with PREVAIL-imaging risk stratification pathway to risk stratify in terms of cancer risk (low, intermediate and high risk), serum tumour markers and patient presentation which will dictate the appropriate treatment. Those with metastatic disease will have their treatment decision based on ctDNA result, radiology and patient characteristics after discussion between the treating clinician and patient	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Gastrointestinal Stromal Tumour Cohort; Those with suspected Gastrointestinal Stromal Tumour Cohort (GIST) are eligible for this study. KIT and PDGFR mutation detected using ctDNA in conjunction with radiological features will be supportive of a diagnosis of GIST. This may allow for the use of directed targeted therapy, or prioritise surgical resection in some cases. Patients with histological diagnosis will not be eligible for this study. However, patients with inadequate tissue for KIT/PDGFR analysis will be eligible for PREVAIL-ctDNA to confirm the diagnosis of GIST and help guide treatment decisions	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Lung Cancer Cohort; The use of ctDNA in the diagnosis and adaptive management of patients with lung cancer is well established, however not funded by NHS. As aerosol-generating bronchoscopy procedures have reduced due to the COVID-19 pandemic, patients with suspected lung cancer may be offered ctDNA to support the diagnosis. A positive ctDNA result in conjunction with radiological findings will assist in prioritising those suitable for upfront surgical resection, radiotherapy or systemic anti-cancer treatment. It may provide sufficient genotypic information to guide standard of care targeted therapies (usually two tests are required - biopsy and then next generation sequencing of extracted DNA), including in patients without sufficient tissue for EGFR and ALK testing which can be detected using ctDNA. The use of ctDNA to guide treatment decisions in this cohort will not require signed consent as it is considered a standard approach (not yet NHS funded)	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Colorectal Cancer Cohort; Patients with suspected colorectal cancer will often be referred following either suspicion on imaging or faecal immunochemical testing (FIT). FIT testing results will be used to prioritise patients for screening colonoscopy, in conjunction with the PREVAIL-imaging risk stratification pathway	Other: ctDNA blood sampling; Screening/baseline blood sample to be analysed for ctDNA
Part 2 Cohort; Patients with suspected advanced pancreatic or biliary tract cancer who have ctDNA via the ACCESS implementation pathway. The results must be deemed consistent with or diagnostic of pancreatic/biliary tract cancer by the molecular tumour board, discussed at central MDT and the patient cannot have a histological diagnosis.

Outcome Measures

Primary Outcome Measures :

1. ctDNA detection rate within different cancer types (and overall) [ Time Frame: Throughout study completion, up to one year ]
   The primary endpoint, ctDNA detection rate, overall and within different cancer types will be presented as a proportion of patients with a positive ctDNA test out of those tested, with 90% confidence intervals
2. PREVAIL ctDNA Part 2 Study [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Primary end point, Proportion of patients with detectable ctDNA which supports a diagnosis of malignancy and commence treatment

Secondary Outcome Measures :

1. Proportion of patients with a positive ctDNA result which identified a diagnosis and/or commenced treatment [ Time Frame: Throughout study completion, up to one year ]
   All secondary endpoints will be analysed in the patients diagnosed with suspected cancer, i.e. positive ctDNA result, unless stated. They will also be presented overall and by cancer type. The proportion of patients with positive ctDNA result which identified a diagnosis and/or commenced treatment will be presented as a proportion with 90% confidence intervals
2. Proportion of patients with a positive ctDNA result which assisted in prioritising invasive diagnostic tests [ Time Frame: Throughout study completion, up to one year ]
   Proportion of patients with positive ctDNA result which assisted in prioritising invasive diagnostic tests will be presented as a proportion with 90% confidence intervals
3. The association of ctDNA result (positive versus negative) and the PREVAIL-imaging pathway scoring result [ Time Frame: Throughout study completion, up to one year ]
   The association between ctDNA result (positive versus negative) and the PREVAIL-imaging pathway scoring result will be assessed descriptively by presenting cross-tabulations and relevant proportions
4. Estimation of the cost of liquid biopsy in lieu of tissue biopsy as compared to standard of care investigations and treatments prioritisation [ Time Frame: Throughout study completion, up to one year ]
   Simple estimation of the cost of liquid biopsy in lieu of tissue biopsy as compared to standard of care investigations and treatments prioritisation will be performed
5. PREVAIL ctDNA Part 2 Study secondary end point 1a [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Treatment response objective response rate
6. PREVAIL ctDNA Part 2 Study secondary end point 1b [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Progression free survival
7. PREVAIL ctDNA Part 2 Study secondary end point 1c [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Overall survival
8. PREVAIL ctDNA Part 2 Study secondary end point 2 [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Proportion of patients who undergo a repeated invasive procedure
9. PREVAIL ctDNA Part 2 Study secondary end point 3a- comparison with NHS targets [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
   Comparison of diagnostic pathway duration with NHS faster Diagnostic Standard (FDS)
10. PREVAIL ctDNA Part 2 Study secondary end point 3b- comparison with NHS targets [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Comparison of diagnostic pathway duration with 62 day wait target
11. PREVAIL ctDNA Part 2 Study secondary end point 4a [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Type of complications from invasive diagnostic procedures
12. PREVAIL ctDNA Part 2 Study secondary end point 4b [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Frequency of complications from invasive diagnostic procedures
13. PREVAIL ctDNA Part 2 Study secondary end point 4c [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Severity of complications from invasive diagnostic procedures
14. PREVAIL ctDNA Part 2 Study secondary end point 5 [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Number and type of invasive procedures performed
15. PREVAIL ctDNA Part 2 Study secondary end point 5b [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Number of histopathology reviews
16. PREVAIL ctDNA Part 2 Study secondary end point 5c [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Number of tissue based NGS performed
17. PREVAIL ctDNA Part 2 Study secondary end point 6a [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Healthcare costs associated with diagnostic pathway
18. PREVAIL ctDNA Part 2 Study secondary end point 6b [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Cost per-quality adjusted-life-year of diagnostic pathway
19. PREVAIL ctDNA Part 2 Study secondary end point 6c [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Number of hospital visits in diagnostic pathway
20. PREVAIL ctDNA Part 2 Study secondary end point 6d [ Time Frame: To run parallel for 12 months alongside the ACCESS implementation programme ]
    Length of hospital stay during diagnostic pathway

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Patients with suspected malignancy for whom invasive biopsy for definitive histological diagnosis is challenging either due to COVID-19-related resource limitations, infection control or technical feasibility will be considered for this study

Criteria

Inclusion Criteria:

• Participants aged ≥18 years old
• Patients with suspected malignancies of early stage colorectal cancer (FIT intermediate and high risk), early and late stage pancreatic cancer, biliary tract cancer, gastro-intestinal stromal tumours, lung cancer or bladder cancer, without a definitive histological diagnosis (including those with inconclusive biopsy result) or
• Patients with histological diagnosis of lung cancer without adequate tissue for NHS genomic test directory predictive biomarker testing
• Ability to provide informed consent.
• Patients with performance status suitable for oncological treatments (ECOG performance status 0-2).

Exclusion criterion:

• Patients with an established histological diagnosis adequate to support standard of care treatment

PART 2:

Inclusion criteria

• Included in the ACCESS implementation programme
• Has detectable ctDNA on Guardant360© assay
• Discussion at molecular tumour board and central multi-disciplinary meeting confirming ctDNA variant is supportive of diagnosis of PC/BTC (diagnostic or consistent with)
• Performance status suitable for oncological treatment
• Ability to provide informed consent

Exclusion criteria

1. Previously diagnosed invasive or haematological malignancy within the past 3 years
2. Outcome at the molecular tumour board not supportive of cancer diagnosis (possibly consistent or not consistent)

Contacts and Locations

Contacts

Contact: Naureen Starling, MBBS MRCP MD; 0208664778; Naureen.Starling@rmh.nhs.uk

Contact: Richard Crux, CIBiol; 02086426011; Richard.Crux@rmh.nhs.uk

Locations

United Kingdom

Royal Marsden Hospital; Recruiting

Sutton, Surrey, United Kingdom, SM2 5PT

Contact: Naureen Starling +44 020 7352 8171 naureen.starling@rmh.nhs.uk

Sponsors and Collaborators

Royal Marsden NHS Foundation Trust

Investigators

• Principal Investigator: Justin Mencel, MBBS; Royal Marsden Hospital NHS Foundation Trust

More Information

• Responsible Party: Royal Marsden NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT04566614
• Other Study ID Numbers: CCR 5292
• First Posted: September 28, 2020
• Last Update Posted: February 22, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Biliary Tract Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Gastrointestinal Stromal Tumors; Urinary Bladder Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Biliary Tract Diseases; Lung Diseases; Respiratory Tract Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases