Clinical trial NCT04049747: Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer
Official title: Imperial Prostate 4: Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Prostate Cancer
Non-metastatic Prostate Cancer
Prostate Adenocarcinoma
Keywords: Prostate Cancer
prostate adenocarcinoma
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Prostate Cancer UK
name: Imperial Clinical Trials Unit (ICTU)
First posted: 2019-08-08
Enrollment: 100
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two linked Randomised Controlled Trials with CHRONOS-A and CHRONOS-B discussed with patients and choice of A or B dependent on physician and patient equipoise.

* CHRONOS-A Two arm RCT
* CHRONOS-B Multi-Arm Multi-Stage (MAMS) Randomised Control Trial
Primary purpose: TREATMENT

Brief summary: Men diagnosed with significant cancer confined to the prostate currently undergo radical therapy directed to the whole prostate (radiotherapy or prostatectomy). These provide good cancer control but can cause significant side effects.

Focal Therapy involves targeting the cancer alone, whilst leaving healthy prostate gland alone. Case series have shown similar cancer control over 5 years with a much better side effect profile. However, there have been no randomised control trials (RCTs) comparing the success in cancer control and the quality of life in patients that undergo radical therapy vs those that undergo focal therapy. Further, there is a need to assess the use of additional therapies that may improve the cancer control outcomes following focal therapy. By having a trials platform with two RCTs (CHRONOS-A and CHRONOS-B) that reflect best patient and physician preferences/ equipoise, the investigators aim to answer these questions.

To improve acceptability, recruitment and compliance, the investigators have an embedded study aimed at reviewing clinician and patient perspectives and trial acceptability. CHRONOS-A will compare radical therapy to focal therapy, whilst CHRONOS-B will compare focal therapy alone to focal therapy with various therapies targeting the testosterone pathway that can shrink the cancer before it is treated. The investigators think this might improve outcomes further for men that definitely want focal therapy.

Detailed description: AIM:

CHRONOS-A

Pilot: To determine if men will agree to participate in a randomised controlled trial that randomly assigns them to focal therapy alone or radical therapy (radiotherapy or prostatectomy).

Main: To determine if focal therapy alone is non-inferior when compared to radical therapy (radiotherapy or surgery) in terms of progression-free survival at 5 years in men with clinically significant non-metastatic cancer.

CHRONOS-B

Pilot: To determine if men expressing a preference for focal therapy will agree to participate in a multi-arm, multi-stage Randomised Controlled Trial that randomly assigns them to focal therapy alone or focal therapy in combination with neoadjuvant and/or adjuvant agents.

Main: To determine if focal therapy combined with neoadjuvant and/or adjuvant agents, compared to focal therapy alone, will improve failure-free survival at 5 years, in men with clinically significant non-metastatic cancer.

OBJECTIVES To deliver a trials framework that fits with existing patient and physician equipoise so that the investigators can answer the next generation of research questions to evaluate medium-term outcomes following minimally invasive focal therapy in the treatment of clinically significant, non-metastatic prostate cancer.

Embedded internal pilot objectives:

* Determine patient acceptance to randomisation.
* Conduct an embedded qualitative study of patient and clinician acceptance and experience of the linked randomised controlled trial CHRONOS design.
* Establish the feasibility of an economic evaluation alongside the main trial.
* Determine acceptability and completeness of resource use and utility measures.
* Identify the relevant NHS and non-NHS resource use to be collected alongside the main trial.
* Identify the relevant items to populate the Cost and Consequences framework.
* Perform preliminary analysis of pattern of missing data.

MAIN STUDY PRIMARY OBJECTIVES

CHRONOS-A:

To evaluate progression-free survival rates of focal therapy alone compared to radical therapy (radiotherapy or surgery) in the treatment of non-metastatic clinically significant prostate cancer. Progression-free survival is defined as time from randomisation to salvage whole-gland or systemic therapy, prostate cancer metastases or prostate cancer-specific mortality.

CHRONOS-B:

To evaluate Failure-Free-Survival rates of focal therapy alone compared to focal therapy combined with other therapies as a neoadjuvant strategy. Failure-Free-Survival is defined as time from randomisation to further focal therapy session or salvage whole-gland or systemic therapy or prostate cancer metastases or prostate cancer-specific mortality.

MAIN STUDY SECONDARY OBJECTIVES

Disease control:

Determine the histological, biochemical and oncological disease control for men undergoing radical therapy, focal therapy or focal therapy with neo/adjuvant treatments.

Adverse events and Functional Outcomes:

Determine the adverse events and functional outcomes after radical therapy, focal therapy or focal therapy with neo/adjuvant treatments

Health economics:

* Establish the NHS costs of the different interventions.
* Determine the Cost per QALYs (CUA), cost per PFS/FFS (CEA) and cost and consequences (CCA).
* Determine acceptability and completeness of resource use and utility measures.

Qualitative:

* Patient experience of consent and recruitment, including reasons for declining participation.
* Participants' motivation to accept randomisation to and compliance with an intervention, which may or may not include neoadjuvant and adjuvant treatments.
* Patients' understanding and experience of each trial arm.
* Patients' experience of toxicities, focusing on erectile dysfunction and urinary symptoms.
* Patients' attitudes to the predicted survival rate.
* Potential improvements to recruitment processes.
* Healthcare professionals' attitudes to intervention arms and trial design and whether this might impact on recruitment.

Imaging and Histology:

* Compare MRI outcomes with histology at time-points in which both are mandated.

Biobank and databank objectives:

* Evaluate cancer infiltrating immune cells and immune gene signatures following ablation.
* Build a biobank and databank of matched imaging, blood, serum, plasma and pre-digital rectal examination urine as well as FFPE biopsy samples.

DURATION :

Pilot: Recruitment 12 months. Minimum 3 months follow-up. Main study: Recruitment further 48 months. Total including follow-up = 96 months

SAMPLE SIZE :

Pilot Study - CHRONOS-A \& B - 60 patients each over 12-months. Main study - CHRONOS-A - 1190 patients / CHRONOS-B - 1260 patients. PATIENT POPULATION: Men with non-metastatic prostate cancer who are suitable for focal therapy and radiotherapy.

PRIMARY ENDPOINTS (Main Stage) CHRONOS-A: Progression-Free survival (PFS) defined as biochemical failure (radical therapies only) or salvage therapy (local or systemic) or prostate cancer metastases or prostate cancer specific mortality.

CHRONOS-B: Failure-Free survival (FFS) defined as more than one focal therapy session or salvage therapy (local or systemic) or prostate cancer metastases or prostate cancer specific mortality.

SECONDARY ENDPOINTS (Main Stage)

Disease control:

* Rates of positive biopsy for any prostate cancer and significant cancer defined by a number of different thresholds on biopsy following focal therapy (treated and untreated side).
* Rates of second or third focal therapy sessions, in-field or out-of-field.
* Rates of radiotherapy as adjuvant or salvage therapy following surgery or focal therapy.
* Rates of prostatectomy as adjuvant or salvage therapy following radiotherapy or focal therapy.
* Rates of systemic therapy as adjuvant or salvage therapy following surgery, radiotherapy or focal therapy.
* Rates of prostate cancer-specific mortality.
* Rates of all-cause mortality.
* Long-term health outcomes of those participants consenting to longitudinal follow-up will be reported in subsequent studies pending further funding.

Adverse events and functional outcomes:

* Rates of cystoscopic interventions following treatment.
* Rates of implant insertion for treatment of incontinence and erectile dysfunction.
* Rates of medication and/or pump devices used for erectile dysfunction following treatment.
* Rates of endoscopic investigations of the lower bowel following treatment.
* Rates of pad-use and quantity per day for urinary incontinence following treatment.
* Rates of pad-use and quantity per day for faecal incontinence following treatment.
* Rates of adverse event rates and complications.
* Genito-urinary and rectal side-effects using patient-reported outcome measures using validated questionnaires including evaluation of return to baseline function for erectile and urinary function and various minimum decreases in PROMS scores.

Health economics:

* To establish the NHS costs of the different interventions.
* To determine the incremental cost per quality adjusted life year (QALYs)gained over the estimated lifetime of participants for focal therapy versus radical therapy.
* To determine the incremental cost per quality adjusted life year (QALYs) gained over the estimated lifetime of participants for focal therapy versus focal therapy with neoadjuvant and/or adjuvant strategies.

Qualitative:

* The impact on participants' overall health-related quality-of-life including adverse events and impact on genito-urinary and rectal functional status using validated patient reported outcome measures.
* Descriptive analyses of the questionnaire data, and use of questionnaire and qualitative interview datasets in a multi-methods analysis to look for overarching themes in barriers and facilitators to participation in CHRONOS-A and CHRONOS-B.

Imaging and Pathology

* Accuracy and variability of multi-parametric MRI (mpMRI) in detecting disease at baseline prior to focal therapy and absence or presence of recurrence of cancer based on histology outcomes on biopsy. Target definition for recurrence will be defined as significant prostate cancer as per inclusion criteria.

Translational, Biobank and Databank:

* Analysis on the localisation and nature of cancer-infiltrating immune cells and the immune-relevant gene expression within the cancer tissue.
* The creation of a biobank and databank of matched blood, serum, plasma and pre-digital rectal examination urine as well as imaging as well as FFPE biopsy samples.

Eligibility criteria: Inclusion Criteria:

* PSA \</=20ng/ml
* Patients must have undergone a diagnostic pre-biopsy MRI compliant with national uro-radiology consensus guidelines. Dynamic contrast enhancement using gadolinium is not required at diagnostic stage. However, contrast enhancement MRI will be required in those men who undergo focal therapy prior to focal therapy as a baseline for comparison during follow-up. In the absence of a compliant MRI (for clinical or other reasons), a transperineal template mapping biopsy using a 5-10 mm sampling frame will be required
* Histologically proven prostate adenocarcinoma
* Overall Gleason score of 7 (either 3+4=7 or 4+3=7) of any length or Gleason 3+3=6 provided \>/=6mm cancer core length in any one core. Patients with Gleason 4+4=8 in some cores but where the overall Gleason score is 7 will be included.
* Bilateral histologically proven prostate cancer is permissible provided the following criteria are met:

  * The index lesion to be treated if focal therapy is used meets the above histological criteria.
  * The patient may have a PIRADS or Likert score 3, 4, 5 mpMRI lesion on the same hemi-gland (either right/left or anterior/posterior) as the histological index lesion
  * Secondary areas of Gleason 3+3=6 of \</=5mm cancer outside of the treatment field can be monitored, if present, and patient undergoes focal therapy.
  * If a Likert or PIRADS score 3,4 or 5 mpMRI lesion is present in an area outside of the treatment field with a negative biopsy for cancer then pathology must be reviewed and confirm the presence of inflammation or atrophy if the patient is to undergo focal therapy\*
* Radiological stage T2b/T3a will require central review regarding suitability for focal therapy.
* Index tumour volume, as seen on mpMRI if carried out, will be restricted to 50% of one lobe for either unilateral or bilateral ablation, patients with tumour volume \>/=50% of one lobe will require central review prior to enrolment. Final decisions on suitability of focal therapy will lie with the trial central review in these cases.
* No restriction exists in CHRONOS-A on previous or current use of 5-alpha reductase inhibitors or anti-androgens or LHRH agonists or LHRH antagonists.
* Age at least 18 years of age
* Participants must be fit to undergo all procedures listed in the protocol as judged by clinical team

Exclusion Criteria:

* Previous or current LHRH agonist or LHRH antagonist or anti-androgen use in CHRONOS-B.
* Patients already established on a 5 alpha-reductase inhibitor (finasteride or dutasteride) who wish to go into CHRONOS-B will need to discontinue this for at least 6 months prior to randomisation. (NB: testosterone supplementation is permitted)
* Previous treatment for prostate cancer
* Life expectancy is likely to be less than 10 years
* Unable to give informed consent

Primary outcomes:
measure: Pilot: Acceptance of Randomisation to Allocated Arm Within CHRONOS A & CHRONOS B
timeFrame: 12 months
measure: Pilot: Recruitment Rate to CHRONOS A & CHRONOS B and Their Corresponding 95% Confidence Intervals
timeFrame: 12 months
measure: Pilot: Treatment Compliance to CHRONOS - A
timeFrame: 12 months
measure: Pilot: Treatment Compliance (CHRONOS-B)
timeFrame: 12 months
measure: Drug Compliance to CHRONOS-B Only
timeFrame: 12 months
measure: Pilot: Randomisation Rate to CHRONOS A & CHRONOS B and Their Corresponding 95% Confidence Intervals
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Brixton
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: London
city: Isleworth
country: United Kingdom
facility: West Middlesex Hospital
state: Middlesex
city: High Heaton
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
state: Newcastle Upon Tyne
city: Chertsey
country: United Kingdom
facility: Ashford & St Peter's Hospitals (ASPH) NHS Foundation Trust
state: Surrey
city: Basingstoke
country: United Kingdom
facility: Hampshire Hospital NHS Foundation Trust
city: Kingston upon Thames
country: United Kingdom
facility: Kingston Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Sunderland
country: United Kingdom
facility: South Tyneside and Sunderland NHS Foundation Trust
Study officials:
affiliation: Imperial College London
name: Hashim Ahmed
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reddy D, Shah TT, Dudderidge T, McCracken S, Arya M, Dobbs C, Emberton M, Fiorentino F, Day E, Prevost AT, Staffurth J, Sydes M, Winkler M, Ahmed HU. Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial. Contemp Clin Trials. 2020 Jun;93:105999. doi: 10.1016/j.cct.2020.105999. Epub 2020 Apr 14.