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PAN-study: Pan-Cancer Early Detection Study (PAN)

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ClinicalTrials.gov Identifier: NCT03756597
Recruitment Status : Recruiting
First Posted : November 28, 2018
Last Update Posted : November 28, 2018
Sponsor:
Collaborators:
Cambridge University Hospitals NHS Foundation Trust
Cancer Research UK
Information provided by (Responsible Party):
Owlstone Ltd

Brief Summary:

The PAN Cancer Early Detection study is a prospective cross-sectional observational case-control study evaluating whether Breath Biopsy (developed by Owlstone Medical Ltd.; the Sponsor of this study) can differentiate between patients with and without different cancer types, by comparing breath biomarkers of patients with gastric, oesophageal, pancreatic, renal, prostate and bladder cancer from matched controls. In total 82 cases (cancer) and 82 matched controls for each tumour type will be recruited at Cambridge University Hospitals NHS Foundation Trust, with an additional 164 healthy volunteers. Participants who consented to participation will be asked to provide 1 breath sample, using the ReCIVA breath collector (developed by Owlstone Medical Ltd. and CE-marked). For controls and cases,medical metadata (general medical history) will be collected as well as information on the diagnostic work-up and follow up data (general health data, details on therapy response for patients with confirmed cancer diagnosis, development of a malignancy during follow-up for matched controls) on the basis of the participant's medical charts. Follow-up data will be collected up to 12 months after the breath sample was collected. For healthy volunteers, clinical metadata and a telephone based follow up at 6 and 12 months will be collected. In a small subset of 15% of the participants, up to additional 4 breath samples will be collected to contribute to the development of a validated assay that can then be validated in further studies.

The anonymised breath samples will be analysed at the clinical laboratories of Owlstone Medical Ltd. in Cambridge. The study is a collaboration effort between Owlstone Medical Ltd., Cancer Research UK and University Cambridge Hospitals NHS Foundation.


Condition or disease Intervention/treatment
Gastric Cancer Esophageal Cancer Renal Cancer Prostate Cancer Bladder Cancer Pancreatic Cancer Device: ReCIVA Device: CASPER

Detailed Description:

There is a pressing need for techniques that allow detection of cancer at an earlier stage when curative treatment is more likely. Exhaled biomarkers are known to reflect a wide range of metabolic processes, including those related to cancer such as the Warburg effect. Owlstone Medical Ltd (hereafter referred to as Owlstone Medical) has developed Breath Biopsy; a workflow to collect and analyse breath Volatile Organic Compounds (VOCs) in a highly standardised way. The PAN-study is a collaborative effort between Cambridge University Hospitals NHS Foundation Trust (CUH), University of Cambridge (UoC), Cancer Research United Kingdom (CRUK) and Owlstone Medical to evaluate the potential of Breath Biopsy to detect various types of cancer by profiling breath metabolites.

The PAN-cancer Early Detection study or PAN-study is a prospective cross-sectional observational case-control study evaluating whether Breath Biopsy can differentiate between patients with and without different cancer types by comparing breath biomarkers for a range of cancer types including patients with gastric, oesophageal, pancreatic, renal, prostate and bladder cancer. Subjects with a histologically confirmed cancer will be recruited from CUH by local research staff. Breath samples will be collected by means of the ReCIVA breath sampler which requires tidal breathing into a face mask for around 10 minutes. A cancer free control subject matched for age, sex and tumour specific risk factors will be recruited and sampled. Breath samples will be shipped to Owlstone Medical for analysis of breath biomarkers by Gas Chromatography-Time Of Flight-Mass Spectrometry (GC-TOF-MS) and Gas Chromatography-Field Asymmetric Ion Mobility Spectrometry (GC-FAIMS).

This study will be the first step towards evaluating VOCs analysis as a test to improve early detection rates for cancer with future applicability to primary care. Ultimately, such a research program could enable low cost and widespread targeted screening programs for cancer.


Study Type : Observational
Estimated Enrollment : 1134 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: PAN-study: Pan-Cancer Early Detection Study
Actual Study Start Date : September 26, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Group/Cohort Intervention/treatment
Cases

Case pathway A - Intention to diagnose population

Only patients with a very high clinical suspicion based on imaging are scheduled for surgical procedures.Subjects with a confirmed diagnosis of cancer after clinical work-up will be labelled cases. of the study.

Patients with a Prostate, Bladder, Gastric or Oesophageal cancer will be recruited after confirmation of their diagnosis but prior to initiation of therapy.

Device: ReCIVA
The ReCIVA breath sampler contains a CO2 and pressure sensor, which allows the operator to monitor the breath sampling procedure and patient comfort. Both the operator and the patient can pause or abort the breath sampling procedure within seconds by removing the mask. The time investment required from patients is approximately 15 minutes for consenting and medical history and 10 minutes per breath collection.

Device: CASPER
Minimizes contamination of breath samples by external VOCs Removes need for clean air supply line

Clinical Controls

Clinical controls represent subjects that:

  • Are suspected of the same cancer or part of an at risk-group
  • Have undergone full per-guideline diagnostic work-up, resulting in confirmation the subject does not have cancer (see section 6)
  • Is matched to the case for age, gender and known risk-factors specific to that tumour type (section 5.4)
Device: ReCIVA
The ReCIVA breath sampler contains a CO2 and pressure sensor, which allows the operator to monitor the breath sampling procedure and patient comfort. Both the operator and the patient can pause or abort the breath sampling procedure within seconds by removing the mask. The time investment required from patients is approximately 15 minutes for consenting and medical history and 10 minutes per breath collection.

Device: CASPER
Minimizes contamination of breath samples by external VOCs Removes need for clean air supply line

Healthy volunteers
Healthy volunteers will be recruited from the clinical research facility at Addenbrooke's Hospital (Cambridge) or from the Cambridge BioResource. These subjects will be selected to have a similar age and sex distribution as the overall PAN-study cases.
Device: ReCIVA
The ReCIVA breath sampler contains a CO2 and pressure sensor, which allows the operator to monitor the breath sampling procedure and patient comfort. Both the operator and the patient can pause or abort the breath sampling procedure within seconds by removing the mask. The time investment required from patients is approximately 15 minutes for consenting and medical history and 10 minutes per breath collection.

Device: CASPER
Minimizes contamination of breath samples by external VOCs Removes need for clean air supply line




Primary Outcome Measures :
  1. Ability of the breath-test to discriminate between patients with and without any cancer or a specific tumour type using GC-FAIMS and GC-TOF-MS [ Time Frame: 3 years ]
    The ability of the breath-test to discriminate between patients with and without any cancer or a specific tumour type will be investigated for both the GC-FAIMS and GC-TOF-MS data separately. A similar approach will be taken for both datasets: Data will be curated after clinical and technical monitoring to assure maximum validity of the data utilised to construct the algorithm.After curation subjects will be partitioned into a 2:1 training and validation set split equally between cases and controls. This partitioning will be done en bloc for cases and matched controls. Model selection will be conducted in the training set with a 10-fold internal cross-validation to reduce model overfitting. Subsequently, the validation set will be utilised to estimate the performance of the model in an independent sample.


Secondary Outcome Measures :
  1. Patient feedback on usability and acceptability of Breath Biopsy as assessed using a a structured interview [ Time Frame: 3 years ]
    • Patient feedback on usability and acceptability, including willingness to participate.
    • Qualitative review of barriers to adoption for study subjects and health professionals.

    Initial data-analysis will be performed after the diagnostic work-up has been completed for study subjects and sufficient subjects have been recruited into a single study group. The metadata and classification of subjects can be updated up to 6 months after breath sampling based on the data obtained through chart-based follow-up.

    Qualitative analysis of the secondary study endpoints will utilise all recruited subjects including those excluded from the biomarker analysis.



Other Outcome Measures:
  1. Measure the influence of tumour phenotype on Volatile Organic Compounds (in breath) [ Time Frame: 3 years ]
    The association between location of the primary tumour (e.g. renal, gastric) and exhaled VOCs will be studied


Biospecimen Retention:   Samples Without DNA
Patients will inhale room air from which environmental VOCs have been removed to prevent contamination of the sample. The mask contains a CO2 sensor that drives two micro-pumps in the mask that sample alveolar and bronchial breath separately. This is relevant because different cancer biomarkers can be found in different portions of breath. During the procedure the breath will automatically be sampled onto four sorbent tubes to collect a total of 1.5L of breath. The procedure will normally take around 10 minutes, very rarely exceeding 15 minutes if exhaled volumes are small. After collection, the sorbent tubes are stored in the refrigerator at 4-8°C until shipment to Owlstone Medical.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
The inclusion and exclusion criteria for the various study populations are detailed above. General inclusion and exclusion criteria which apply to all study subjects are detailed followed by indication specific criteria are also detailed for both inclusion and exclusion.
Criteria

5.1. General inclusion criteria

  1. Aged 45 years or over
  2. Ability to provide informed consent

5.2. General exclusion criteria

  1. (Anticipated) inability to complete the breath sampling procedure due to e.g. inability to maintain adequate ventilation unaided or claustrophobia
  2. Participation in a Clinical Trial Investigational Medicinal Product (CTIMP) during the 3 months prior to breath biopsy.
  3. Any biopsy or endoscopic procedure conducted during the past 48 hours. A breath sample can be collected >48 hours post procedure.
  4. Any disorder that is not stable in the opinion of the investigator. Specifically, subjects should be excluded if:

    4.1. Currently in the process of investigation for a malignancy other than the tumours of interest to this study.

    4.2. A history of malignancy unless the subject has been in remission at least 2 years prior to inclusion. Patients previously treated for highly localised disease e.g. basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided that curative therapy was completed at least 12 months prior to inclusion.

    4.3. A history of the malignancy the patient is currently being investigated for. E.g. a patient suspected of bladder cancer with previous bladder cancer in medical history.

    4.4. Known active bacterial, fungal or viral infection including but not limited to upper respiratory tract infection, tuberculosis, pneumonia, cystitis, pyelonephritis, gastritis or hepatitis. Patients can be recruited after being symptom free for at least 2 weeks for mild infections and 6 weeks if admitted to the hospital and/or treated with i.v. antibiotics.

    4.5. Documented history of a clinically important lung condition other than asthma or COPD e.g., active lung infection, α1- antitrypsin deficiency, bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis/mycosis, pulmonary fibrosis or hypersensitivity pneumonitis.

    4.6. Asthma or COPD exacerbation requiring hospitalisation and/or administration of oral prednisolone in past 6 weeks.

    4.7. Renal failure Stages 3 and above (GFR 30-60mL/min).

    4.8. Any hospitalisation for symptoms unrelated to the clinical presentation of the tumour under investigation during the past 6 weeks.

  5. Immunocompromised patients: specifically, patients with Acquired Immune Deficiency Syndrome (AIDS) (HIV with normal blood counts is eligible), inborn or acquired severe immune-deficiency including those caused by pharmacological treatment.
  6. Documented history of pulmonary surgery or endobronchial interventional procedures other than biopsy, lavage or bronchial brushings. These include surgical resection, VATS, bronchial thermoplasty and coiling.

    5.3 Indication specific selection criteria

    Pancreatic cancer

    Case inclusion criteria • Scheduled for surgical removal of a tumour suspected to be an exocrine ductal adenocarcinoma of the pancreas

    Control inclusion criteria. • Subjects with normal endoscopy or EUS and normal CT-abdomen

    Control exclusion criteria • Active acute pancreatitis

    Renal cancer

    Case inclusion criteria • Scheduled for surgical removal of a tumour suspected to be renal cancer

    Control inclusion criteria

    • Subjects investigated for dipstick haematuria with a normal cystoscopy and renal imaging (controls identical to bladder controls).

    Prostate cancer

    Case inclusion criteria • Subject with histologically confirmed high-risk prostate cancer falling into category 4 or 5 based on a validated prognostic scoring system based on the NICE criteria18.

    a. Category 4: Any of the following conditions should apply: i. Gleason 8 (prognostic score 4) ii. PSA > 20ng/ml iii. Stage T3

    b. Category 5: Any of the following conditions should apply: i. Group A: At least two of the following:

  1. Gleason 8 (prognostic score 4)
  2. PSA > 20ng/ml
  3. Stage T3 ii. Group B: Any Gleason 9-10 (prognostic score 5) iii. Group C: Any stage T4

    Case exclusion criteria

    • Initiation of treatment for prostate cancer

    Control inclusion criteria

    • Subjects receiving a prostate biopsy under clinical suspicion of prostate cancer, without evidence of malignancy.

    Bladder

    Case inclusion criteria

    • Histologically confirmed muscle invasive or metastatic urothelial bladder cancer

    Case exclusion criteria

    • Initiation of treatment for bladder cancer
    • Macroscopically complete removal of tumour during diagnostic work-up

    Control inclusion criteria • Subjects investigated for dipstick haematuria with a normal cystoscopy and renal imaging (Controls identical to Renal controls)

    Gastric

    Case inclusion criteria • Histologically confirmed gastric cancer

    Control inclusion criteria

    • Referred under clinical suspicion of gastric or oesophageal cancer with a normal gastroscopy, without any signs of Barrett's oesophagus. (Controls in part identical to oesophageal)

    Control exclusion criteria

    • Subjects with gastric ulcer or gastritis as identified upon gastroscopy

    Oesophageal

    Case inclusion criteria

    • Histologically confirmed squamous cell or adenocarcinoma of the oesophagus (including the gastro-oesophageal junction).

    Control inclusion criteria

    • Subject with non-dysplastic Barrett's oesophagus

    Control exclusion criteria

    • Subjects with gastric ulcer or active gastritis identified upon gastroscopy


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03756597


Contacts
Contact: Georgina Karecla 01223 428200 georgina.karecla@owlstone.co.uk
Contact: Alexandra Saedeleer 01223 428200 Alexandra.DeSaedeleer@owlstone.co.uk

Locations
United Kingdom
Cambridge University Hospital NHS Recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Rebecca Fitzgerald, Professor       rcf29@mrc-cu.cam.ac.uk   
Sponsors and Collaborators
Owlstone Ltd
Cambridge University Hospitals NHS Foundation Trust
Cancer Research UK
Investigators
Study Director: Marc P van der Schee, MD, PhD +01223 428200
Study Chair: Prof Rebecca Fitzgerald, MD, PhD Cambridge University Hospital
Principal Investigator: Massimiliano di Pietro, MD, PhD Cambridge University Hospital
Principal Investigator: Mr Vincent J Gnanapragasam, MD, PhD Cambridge University Hospital
Principal Investigator: Mr Grant Stewart, MD, PhD Cambridge University Hospital
Principal Investigator: Dr Godfrey Edmund, MD, PhD Cambridge University Hospital
Principal Investigator: Miss Alexandra Colquhoun,, Colquhoun, Cambridge University Hospital

Additional Information:
Responsible Party: Owlstone Ltd
ClinicalTrials.gov Identifier: NCT03756597     History of Changes
Other Study ID Numbers: PAN
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: November 28, 2018
Last Verified: November 2018

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

Additional relevant MeSH terms:
Pancreatic Neoplasms
Stomach Neoplasms
Urinary Bladder Neoplasms
Esophageal Neoplasms
Kidney Neoplasms
Carcinoma, Renal Cell
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gastrointestinal Neoplasms
Gastrointestinal Diseases
Stomach Diseases
Urologic Neoplasms
Urogenital Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Head and Neck Neoplasms
Esophageal Diseases
Kidney Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type