Hypoxia-driven Prostate Cancer Genomics (HYPROGEN)

NCT ID: NCT05702619

Last Updated: 2023-01-27

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-10-03
• Study Completion Date: 2023-06-30

Brief Summary

Due to the rapid growth, tumour demand for oxygen is often higher than what can be delivered by the newly forming blood vessels. Tumour adaption to this imbalanced oxygen supply and demand (hypoxia) is associated with poor prognosis and genetic changes (genomic instability) that allow it to become more resistant to chemo- and radiotherapy. Patients with hypoxic tumours therefore die earlier. Limited information is available on hypoxia in newly diagnosed prostate cancer, especially to what degree hypoxia in the prostate tumour is associated with the presence of metastases to bones. The Hyprogen trial is a prospective, non-randomised, exploratory biopsy and imaging biomarker study recruiting 60 patients with prostate cancer to better establish the role of hypoxia in prostate cancer cells evolution and early metastatic spread.

Detailed Description

Arm 1 of this study will aim to determine the association between hypoxia in the primary tumour with the presence of skeletal metastases and aim to determine if hypoxia is also present in the metastatic sites themselves. Arm 2 will aim to determine the genetic changes associated with hypoxia in cancers that have not spread outside the prostate. Hypoxia presence will be determined by using a hypoxia identifying stain (by giving a patient a tablet of the stain to take orally) and by identifying genomic alterations that are associated with hypoxia. After taking the tablet of the hypoxia marker (Pimonidazole) patients in Arm 1 will receive both a biopsy of the prostate and of one or two of the bone metastases. The presence or not as well as the degree of hypoxia in both sites will be assessed. Patients in Arm 2 will receive pimonidazole prior to a planned radical prostatectomy and the heterogeneity of hypoxia related genetic change throughout the prostate will assessed. Arm 2 patients will undergo MRI hypoxia imaging to validate the detection of pimonidazole marked hypoxic regions with a non-invasive imaging method.

Conditions

Prostate Cancer; Hypoxia

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Arm 1

Arm 1 - De novo, treatment-naïve metastatic prostate cancer

Optional non-IMP pimonidazole

Intervention Type: DRUG

patients will be asked to ingest an oral formulation of pimonidazole hydrochloride (HCl) (Oral HypoxyprobeTM-1). Pimonidazole HCl is a marker for hypoxia in tumour tissue when ingested as an encapsulated solid. Following oral administration, pimonidazole distributes throughout the body where it covalently binds to normal and tumour tissues that have regions of low oxygen concentrations (pO2 of ≤ 10 mmHg at 37oC). The tissue binding can be visualised by immunohistochemistry / light microscopy. The capsules are to be taken within 8-16 hours (optimal timepoint 12 hours) before the planned first biopsy within Arm 1 and before radical prostatectomy for patients in Arm 2. If the patient refuses the pimonidazole, forgets to take it, or if it is not available, the patient can still participate in the study and their samples will be stained for hypoxia post-biopsy.

CT-guided Bone Biopsy

Intervention Type: DIAGNOSTIC_TEST

A CT-guided biopsy of a bone metastasis that is deemed to be easy to biopsy and in an area without major risk for pathological fracture or bleeding will be taken during the biopsy visit. Patients will receive routine local anaesthetic of the region to be biopsied followed by thorough disinfection of the biopsy site with antiseptic wipes. Patients will be asked to fast on the day of the procedure and to have an intravenous cannula inserted to allow the use of medication causing minimal sedation (for example midazolam and/or fentanyl) during the procedure if required to alleviate discomfort or pain.

TRUS-guided Targeted Transperineal Prostate Biopsy

Intervention Type: DIAGNOSTIC_TEST

Transperineal Prostate Biopsy will be performed following standard clinical practice of local department. This will include pre-operative oral analgesia and prophylactic antibiotic treatment according to local hospital policy for transperineal prostate biopsies.

Whole-body MRI

Intervention Type: DIAGNOSTIC_TEST

Whole-body MR imaging (wbMRI) will be performed once, before or after the biopsy study visit, depending on available examination slots in the Department of Radiology. WbMRI images will allow comparison of the numbers of bone metastases detected by routine bone scan and wbMRI for sensitivity assessment of both techniques for oligometastatic disease.

Baseline bloods - for germline testing

Intervention Type: OTHER

Arm 1 -

• 1-2 x 3.5mL blood samples collected into EDTA tubes for germ line DNA extraction and processing to PBMC for banking and future profiling of immune cell populations
• 1 x 10mL serum tubes for future, biobank related research projects, ie lipidomics, metabolics and microRNA analysis

ARM 2 -

A blood sample (maximum 20ml) will be taken for standard of care blood tests prior to prostatectomy including Full Blood Count, Renal Function and PSA. At the same time these standard of care bloods are taken, additional bloods - a maximum of 30ml - will be taken for research purposes as required for the following downstream analysis:

• Germ line DNA extraction and optional processing to PBMC for banking and future profiling of immune cell populations
• Biobank related research projects, ie lipidomics, metabolics and microRNA analysis

Baseline bloods for CTCs and ct DNA taken at same time as baseline bloods in Arm 1

Intervention Type: OTHER

2 x 10mL Streck cell-free DNA blood collection tubes® for circulating tumour cell (CTC) collection and circulating tumour DNA (ctDNA) extraction.

Post-pimonidazole bloods for CTCs and ctDNA

Intervention Type: OTHER

ARM 1 - 2 x 10mL Streck cell-free DNA blood collection tubes® for circulating tumour cell (CTC) collection and circulating tumour DNA (ctDNA) extraction.

Arm 2

Arm 2 - De novo, treatment- naïve localised prostate cancer planned for radical prostatectomy

Optional non-IMP pimonidazole

Intervention Type: DRUG

patients will be asked to ingest an oral formulation of pimonidazole hydrochloride (HCl) (Oral HypoxyprobeTM-1). Pimonidazole HCl is a marker for hypoxia in tumour tissue when ingested as an encapsulated solid. Following oral administration, pimonidazole distributes throughout the body where it covalently binds to normal and tumour tissues that have regions of low oxygen concentrations (pO2 of ≤ 10 mmHg at 37oC). The tissue binding can be visualised by immunohistochemistry / light microscopy. The capsules are to be taken within 8-16 hours (optimal timepoint 12 hours) before the planned first biopsy within Arm 1 and before radical prostatectomy for patients in Arm 2. If the patient refuses the pimonidazole, forgets to take it, or if it is not available, the patient can still participate in the study and their samples will be stained for hypoxia post-biopsy.

Radical Prostatectomy

Intervention Type: PROCEDURE

Radical Prostatectomy will be performed according to standard of care robotic approach and as relayed to the patient by the attending urologic surgeon. The side effects of the surgery are the ones reported in the literature and the latest participant information leaflet provided prior patient consent (e.g. risk of erection disfunction, incontinence, etc.).

Prostate MRI scans

Intervention Type: DIAGNOSTIC_TEST

Patients within Arm 2 will be offered the option to undergo additional MR imaging of the pelvis in addition to any standard of care imaging acquired. In patients who agree to undergo additional scans, MRI scans will be performed on 2 occasions prior to the radical prostatectomy. MRI scans will be acquired on either the MR sim diagnostic scanner, on the MR Linac scanner or on both.

Baseline bloods - for germline testing

Intervention Type: OTHER

Arm 1 -

• 1-2 x 3.5mL blood samples collected into EDTA tubes for germ line DNA extraction and processing to PBMC for banking and future profiling of immune cell populations
• 1 x 10mL serum tubes for future, biobank related research projects, ie lipidomics, metabolics and microRNA analysis

ARM 2 -

A blood sample (maximum 20ml) will be taken for standard of care blood tests prior to prostatectomy including Full Blood Count, Renal Function and PSA. At the same time these standard of care bloods are taken, additional bloods - a maximum of 30ml - will be taken for research purposes as required for the following downstream analysis:

• Germ line DNA extraction and optional processing to PBMC for banking and future profiling of immune cell populations
• Biobank related research projects, ie lipidomics, metabolics and microRNA analysis

Interventions

Optional non-IMP pimonidazole

patients will be asked to ingest an oral formulation of pimonidazole hydrochloride (HCl) (Oral HypoxyprobeTM-1). Pimonidazole HCl is a marker for hypoxia in tumour tissue when ingested as an encapsulated solid. Following oral administration, pimonidazole distributes throughout the body where it covalently binds to normal and tumour tissues that have regions of low oxygen concentrations (pO2 of ≤ 10 mmHg at 37oC). The tissue binding can be visualised by immunohistochemistry / light microscopy. The capsules are to be taken within 8-16 hours (optimal timepoint 12 hours) before the planned first biopsy within Arm 1 and before radical prostatectomy for patients in Arm 2. If the patient refuses the pimonidazole, forgets to take it, or if it is not available, the patient can still participate in the study and their samples will be stained for hypoxia post-biopsy.

Intervention Type: DRUG

CT-guided Bone Biopsy

A CT-guided biopsy of a bone metastasis that is deemed to be easy to biopsy and in an area without major risk for pathological fracture or bleeding will be taken during the biopsy visit. Patients will receive routine local anaesthetic of the region to be biopsied followed by thorough disinfection of the biopsy site with antiseptic wipes. Patients will be asked to fast on the day of the procedure and to have an intravenous cannula inserted to allow the use of medication causing minimal sedation (for example midazolam and/or fentanyl) during the procedure if required to alleviate discomfort or pain.

Intervention Type: DIAGNOSTIC_TEST

TRUS-guided Targeted Transperineal Prostate Biopsy

Transperineal Prostate Biopsy will be performed following standard clinical practice of local department. This will include pre-operative oral analgesia and prophylactic antibiotic treatment according to local hospital policy for transperineal prostate biopsies.

Intervention Type: DIAGNOSTIC_TEST

Radical Prostatectomy

Radical Prostatectomy will be performed according to standard of care robotic approach and as relayed to the patient by the attending urologic surgeon. The side effects of the surgery are the ones reported in the literature and the latest participant information leaflet provided prior patient consent (e.g. risk of erection disfunction, incontinence, etc.).

Intervention Type: PROCEDURE

Whole-body MRI

Whole-body MR imaging (wbMRI) will be performed once, before or after the biopsy study visit, depending on available examination slots in the Department of Radiology. WbMRI images will allow comparison of the numbers of bone metastases detected by routine bone scan and wbMRI for sensitivity assessment of both techniques for oligometastatic disease.

Intervention Type: DIAGNOSTIC_TEST

Prostate MRI scans

Patients within Arm 2 will be offered the option to undergo additional MR imaging of the pelvis in addition to any standard of care imaging acquired. In patients who agree to undergo additional scans, MRI scans will be performed on 2 occasions prior to the radical prostatectomy. MRI scans will be acquired on either the MR sim diagnostic scanner, on the MR Linac scanner or on both.

Intervention Type: DIAGNOSTIC_TEST

Baseline bloods - for germline testing

Arm 1 -

• 1-2 x 3.5mL blood samples collected into EDTA tubes for germ line DNA extraction and processing to PBMC for banking and future profiling of immune cell populations
• 1 x 10mL serum tubes for future, biobank related research projects, ie lipidomics, metabolics and microRNA analysis

ARM 2 -

A blood sample (maximum 20ml) will be taken for standard of care blood tests prior to prostatectomy including Full Blood Count, Renal Function and PSA. At the same time these standard of care bloods are taken, additional bloods - a maximum of 30ml - will be taken for research purposes as required for the following downstream analysis:

• Germ line DNA extraction and optional processing to PBMC for banking and future profiling of immune cell populations
• Biobank related research projects, ie lipidomics, metabolics and microRNA analysis

Intervention Type: OTHER

Baseline bloods for CTCs and ct DNA taken at same time as baseline bloods in Arm 1

2 x 10mL Streck cell-free DNA blood collection tubes® for circulating tumour cell (CTC) collection and circulating tumour DNA (ctDNA) extraction.

Intervention Type: OTHER

Post-pimonidazole bloods for CTCs and ctDNA

ARM 1 - 2 x 10mL Streck cell-free DNA blood collection tubes® for circulating tumour cell (CTC) collection and circulating tumour DNA (ctDNA) extraction.

Intervention Type: OTHER

Other Intervention Names

Pimonidazole Hydrochloride

Eligibility Criteria

Inclusion Criteria

• Male patients aged 18 years and older
• Histologically proven adenocarcinoma of the prostate (≥cT2) or Highly suspected metastatic prostate cancer
• PSA value of ≥ 20 ng/mL
• Multiple lesions (≥ 5) suspicious of metastatic spread on routine imaging procedures with at least one amenable* to biopsy (cohort A) or oligometastatic bone disease (≥1 to ≤ 4) at routine bone scan with at least one lesion amenable* to biopsy (cohort B)

*e.g. safely to biopsy and expectably providing sufficient tissue yield World Health Organisation (WHO) performance status 0 to 2 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 months

• No prior local and/or systemic treatment for localised prostate cancer
• Willing to donate cancer tissue samples for research purposes (bone metastasis and primary tumour)

• Male patients aged 18 years and older cT¬2-T3 / cN0-N1 / cM0 Any Group Grade (GG) 2-5: this includes Gleason scores 3+4, 4+3, 4+4, 4+5, 5+3, 5+4, 5+5. Any PSA
• Histologically proven adenocarcinoma of the prostate
• Undergoing radical prostatectomy as primary treatment for localised prostate cancer
• World Health Organisation (WHO) performance status 0 to 2 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 months
• No prior local and/or systemic treatment for localised prostate cancer
• Willing to donate cancer tissue samples for research purposes (any metastasis and primary tumour)

Exclusion Criteria

• Involvement in the planning and/or conduct of the study (applies to staff at the study site)
• Previous enrolment in the HYPROGEN study
• As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g. uncompensated respiratory, cardiac, hepatic or renal disease)
• Evidence of any other significant clinical disorder or laboratory finding that made it undesirable for the patient to participate in the study
• Any investigational agents or study drugs from a previous clinical study within 30 days of the first tissue collection
• Prior treatment of localized prostate cancer including radiotherapy and/or androgen-deprivation therapy
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• Contra-indications to MRI (incl. pacemakers etc.)
• Bone metastases in difficult to reach areas or areas which might be at risk for pathological fracture post biopsy as judged by biopsying radiologist / chief investigator
• Increased risk of bleeding as a result of biopsy
• History of bleeding disorders or thrombocytopenia (platelets <100/nL)
• Concomitant treatment with anticoagulant therapy, e.g. warfarin/low molecular weight heparin or Anti-Xa-inhibitors and other NOACs, if temporary cessation medically not justifiable
• Current urinary tract infection (UTI) or prostatitis

ARM 2

• Involvement in the planning and/or conduct of the study (applies to staff at the study site)
• As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g. uncompensated respiratory, cardiac, hepatic or renal disease)
• Any investigational agents or study drugs from a previous clinical study within 30 days of the first tissue collection
• Prior treatment of localized prostate cancer including radiotherapy and/or androgen-deprivation therapy
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• Contra-indications to MRI (incl. pacemakers etc.)

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Prostate Cancer UK

OTHER

Sponsor Role: collaborator

The Christie NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Martin Swinton

Role: CONTACT

m.swinton@nhs.net

07896026629

Fizzah M Ali

Role: CONTACT

fizzah.ali@manchester.ac.uk

Facility Contacts

Martin Swinton

Role: primary

m.swinton@nhs.net

Fizzah M Ali

Role: backup

fizzah.ali@manchester.ac.uk

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

CFTSp155

Identifier Type: -

Identifier Source: org_study_id