Selecting Hypoxic Tumours for Treatment Modification

NCT ID: NCT06787053

Last Updated: 2025-05-29

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

30 participants

Study Classification

OBSERVATIONAL

Study Start Date

2024-10-16

Study Completion Date

2028-05-30

Brief Summary

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Approximately 50% of cancer patients with solid tumours will be treated with radiotherapy. A significant proportion (\>25%) of patients have hypoxic tumours which respond poorly to radiotherapy. Hypoxic tumours have a poor prognosis. This can be improved with treatment intensification. Treatment intensification can be modification with CON (breathing O2-enriched air + oral administration of nicotinamide), chemoradiosensitisation, radiation dose-escalation or additional systemic treatments, significantly improving response of the tumours to radiotherapy. However, there are currently no clinically approved biomarkers to identify hypoxic tumours. Our group has developed and validated gene-expression signature-based biomarkers that identify patients with hypoxic bladder, head and neck , prostate, sarcoma and lung cancers. The bladder cancer gene-expression hypoxia signature has been shown to predict benefit from hypoxia modification using RNA from archived tumour tissue. The main purpose of this study is to demonstrate in at least two cancer types that the hypoxia biomarker predicts benefit from hypoxia modification in real-time.

Detailed Description

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Research Question: Can hypoxia biomarkers personalised treatment improve cancer outcomes?

Cancers that are hypoxic (have a high percentage of regions of low local O2 concentration) are refractory to radiotherapy but benefit from hypoxia modification. However, there are no biomarkers to identify patients with hypoxic tumours. The gold standard for determining tissue O2 concentration is the O2-electrode which takes measurements at several sites within the tumour. However, this necessitates insertion of a needle into multiple regions of the tumour so is invasive and provides only a localised hypoxia status. Other hypoxia biomarkers that identify hypoxia have been derived from cell surface protein expression, gene expression or imaging outputs. Proteins expressed on the tumour cell surface of hypoxic cells include CA9 and glut1 but the expression of these proteins is not specific to hypoxia and is highly heterogeneous within tumours. Whilst expression of HIF1 by hypoxic tumours has been shown not to predict benefit from hypoxia-modification. Gene signatures are a set of genes in which the collective changed expression has been validated to demonstrate diagnosis, prognosis or predict therapeutic response. Gene expression is consistently altered across tumours with high hypoxic fractions meaning that they are robust indicators of hypoxia status.

Using RNA extracted from archived material (Formalin fixed paraffin embedded tumour tissue) our gene-expression signature-based biomarkers for bladder, head and neck, prostate, sarcoma, cervical and lung cancers have been validated by demonstrated prognosis in each of the cancer groups. Further the 24 gene bladder cancer hypoxia signature has been shown to be predictive of benefit from hypoxia modification for patients with hypoxic tumours receiving radiotherapy. A recent review of predictive biomarkers in cancer treatment has shown that this is the only predictive biomarker for hypoxia-modification during radiotherapy.

Hypoxic regions in tumours can also be identified using MRI techniques including O2-senstive MRI (OE-MRI) and Intravoxel incoherent motion imaging. Combining imaging with gene expression data results in more accurate assessment of hypoxic status and identify tumour subtype which further contributes to personalised clinical decisions. MRI-based techniques also facilitate localized personalization approaches, e.g., for hypoxia-directed focal radiotherapy dose escalation.

Primary Question/Objective:

Short objective; to establish trials to test if personalised use of established hypoxia-targeted treatments with radiotherapy improves survival and work with the North West Genomics Hub to progress implementing our tissue hypoxia test for delivery across the NHS.

Medium objective; integrate MR imaging in the workflow for measuring hypoxia in at least two tumour sites.

Secondary Question/Objective:

* Integrate radiological parameters with the hypoxia biomarker for personalising treatment.
* Can blood-based biomarkers be early response biomarkers.

Conditions

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Bladder (Urothelial, Transitional Cell) Cancer Prostate Cancer

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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Bladder

Patients diagnosed with bladder cancer

No interventions assigned to this group

Prostate

Patients diagnosed with prostate cancer

No interventions assigned to this group

Cervix

Patients diagnosed with cervical cancer

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

This will be tumour site dependent.

Bladder:

* Older than age 18 years.
* Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
* Able to give informed consent.

Cervix:

* Older than age 18 years.
* Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
* Able to give informed consent.

Prostate:

* Older than age 18 years.
* Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
* Able to give informed consent.

Exclusion Criteria

This will be tumour site dependent

Bladder:

* Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
* Unable to tolerate MRI scans.
* Pregnancy.

Cervix:

* Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
* Unable to tolerate MRI scans.
* Pregnancy.

Prostate:

* Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
* Unable to tolerate MRI scans
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Manchester

OTHER

Sponsor Role lead

Responsible Party

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Ananya Choudhury

Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ananya Choudhury, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Manchester

Locations

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The Christie NHS Foundation Trust

Manchester, , United Kingdom

Site Status RECRUITING

Countries

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United Kingdom

Central Contacts

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Rachel Reed, MSc

Role: CONTACT

01619184780 ext. 7480

Kimberley Reeves, PhD

Role: CONTACT

01619184780 ext. 7480

Facility Contacts

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Rachel Reed, MSc

Role: primary

01619187480 ext. 7480

Kimberley Reeves, PhD

Role: backup

01619187480 ext. 7480

References

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Swartz JE, Smits HJG, Philippens MEP, de Bree R, H A M Kaanders J, Willems SM. Correlation and colocalization of HIF-1alpha and pimonidazole staining for hypoxia in laryngeal squamous cell carcinomas: A digital, single-cell-based analysis. Oral Oncol. 2022 May;128:105862. doi: 10.1016/j.oraloncology.2022.105862. Epub 2022 Apr 18.

Reference Type BACKGROUND
PMID: 35447566 (View on PubMed)

Batis N, Brooks JM, Payne K, Sharma N, Nankivell P, Mehanna H. Lack of predictive tools for conventional and targeted cancer therapy: Barriers to biomarker development and clinical translation. Adv Drug Deliv Rev. 2021 Sep;176:113854. doi: 10.1016/j.addr.2021.113854. Epub 2021 Jun 27.

Reference Type BACKGROUND
PMID: 34192550 (View on PubMed)

Yang L, Taylor J, Eustace A, Irlam JJ, Denley H, Hoskin PJ, Alsner J, Buffa FM, Harris AL, Choudhury A, West CML. A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients. Clin Cancer Res. 2017 Aug 15;23(16):4761-4768. doi: 10.1158/1078-0432.CCR-17-0038. Epub 2017 Apr 11.

Reference Type BACKGROUND
PMID: 28400426 (View on PubMed)

Yang L, Roberts D, Takhar M, Erho N, Bibby BAS, Thiruthaneeswaran N, Bhandari V, Cheng WC, Haider S, McCorry AMB, McArt D, Jain S, Alshalalfa M, Ross A, Schaffer E, Den RB, Jeffrey Karnes R, Klein E, Hoskin PJ, Freedland SJ, Lamb AD, Neal DE, Buffa FM, Bristow RG, Boutros PC, Davicioni E, Choudhury A, West CML. Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. EBioMedicine. 2018 May;31:182-189. doi: 10.1016/j.ebiom.2018.04.019. Epub 2018 Apr 23.

Reference Type BACKGROUND
PMID: 29729848 (View on PubMed)

Lane B, Khan MT, Choudhury A, Salem A, West CML. Development and validation of a hypoxia-associated signature for lung adenocarcinoma. Sci Rep. 2022 Jan 25;12(1):1290. doi: 10.1038/s41598-022-05385-7.

Reference Type BACKGROUND
PMID: 35079065 (View on PubMed)

Forker LJ, Bibby B, Yang L, Lane B, Irlam J, Mistry H, Khan M, Valentine H, Wylie J, Shenjere P, Leahy M, Gaunt P, Billingham L, Seddon BM, Grimer R, Robinson M, Choudhury A, West C. Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma. Br J Cancer. 2023 Jun;128(12):2307-2317. doi: 10.1038/s41416-023-02265-3. Epub 2023 Apr 21.

Reference Type BACKGROUND
PMID: 37085598 (View on PubMed)

Eustace A, Mani N, Span PN, Irlam JJ, Taylor J, Betts GN, Denley H, Miller CJ, Homer JJ, Rojas AM, Hoskin PJ, Buffa FM, Harris AL, Kaanders JH, West CM. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res. 2013 Sep 1;19(17):4879-88. doi: 10.1158/1078-0432.CCR-13-0542. Epub 2013 Jul 2.

Reference Type BACKGROUND
PMID: 23820108 (View on PubMed)

Other Identifiers

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24_DOG13_38

Identifier Type: -

Identifier Source: org_study_id

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