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Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer

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ClinicalTrials.gov Identifier: NCT04049747
Recruitment Status : Recruiting
First Posted : August 8, 2019
Last Update Posted : February 12, 2020
Sponsor:
Collaborators:
Prostate Cancer UK
Imperial Clinical Trials Unit (ICTU)
Information provided by (Responsible Party):
Imperial College London

Tracking Information
First Submitted Date  ICMJE June 4, 2019
First Posted Date  ICMJE August 8, 2019
Last Update Posted Date February 12, 2020
Actual Study Start Date  ICMJE December 11, 2019
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 7, 2019)
  • Acceptance of randomisation to allocated arm within CHRONOS A & CHRONOS B [ Time Frame: 12 months ]
    To assess the acceptance of randomisation to the allocated arm within CHRONOS A & CHRONOS B using rates of compliance, and rates of withdrawal
  • CHRONOS-A Primary Outcome Measures - progression-free survival (PFS) rates of focal therapy alone compared to radical therapy. [ Time Frame: 60 months ]
    To evaluate progression-free survival (PFS) rates of focal therapy alone compared to radical therapy (radiotherapy or surgery) in the treatment of non-metastatic clinically significant prostate cancer. PFS is defined as time from randomisation to salvage whole-gland or systemic therapy, prostate cancer metastases or prostate cancer-specific mortality.
  • CHRONOS-B Primary Outcome Measures - Failure-Free-Survival (FFS) rates of focal therapy alone compared to focal therapy combined with other therapies. [ Time Frame: 60 months ]
    To evaluate Failure-Free-Survival (FFS) rates of focal therapy alone compared to focal therapy combined with other therapies as a neoadjuvant strategy. FFS 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • Progression (Biochemical / Radiological / Clinical) [ Time Frame: 60 months ]
    Progression on PSA and imaging and impact of clinical features on progression, measured using PSA blood tests
  • Frequency of adverse events as determined by Common Terminology Criteria for Adverse Events. [ Time Frame: 60 months ]
    To observe the frequency of adverse events as determined by Common Terminology Criteria for Adverse Events.
  • Health-related quality-of-life [ Time Frame: 60 months ]
    Health-related quality-of-life, measured using EuroQol (EQ-5D-5L) questionnaire, Score 0-100
  • Urinary side effects, IPSS questionnaire [ Time Frame: 60 months ]
    Urinary side effects, measured using the IPSS questionnaire, Score 0-35
  • Urinary side effects, EPIC-Urinary domain questionnaire [ Time Frame: 60 months ]
    Urinary side effects, measured using the EPIC-Urinary domain questionnaire, Score 0-34
  • Sexual side effects [ Time Frame: 60 months ]
    Sexual side effects, measured using the IIEF15 questionnaire, Score 0-75.
  • Effect on quality of life [ Time Frame: 60 months ]
    Effect on quality of life, measured using the EPIC - 26 questionnaire, Score 0-79
  • Impact of participants' overall health-related quality assessed by validated patient reported outcomes measures [ Time Frame: 60 months ]
    To observe the impact of participants' overall health-related quality- of- life as well as adverse events and impact on genito-urinary and rectal functional status using validated patient reported outcomes measures (International Index of Erectile Function-15, EPIC-26, EPIC Urinary domain, International Prostate Symptom Score and CTCAEv4.0 bowel domain). Further analysis to be performed using qualitative interview datasets in a multi-methods analysis.
  • Comparison of predictive value of different MRI scoring systems against histological outcomes. [ Time Frame: 60 months ]
    To compare the predictive value of the PI-RADS and/or Likert scoring system against histological outcomes in patients treated with localised, clinically significant prostate cancer over at least 5 years.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 7, 2019)
  • Progression (Biochemical / Radiological / Clinical) [ Time Frame: 60 months ]
    Progression on PSA and imaging and impact of clinical features on progression, measured using PSA blood tests
  • Frequency of adverse events as determined by Common Terminology Criteria for Adverse Events. [ Time Frame: 60 months ]
    To observe the frequency of adverse events as determined by Common Terminology Criteria for Adverse Events.
  • Health-related quality-of-life [ Time Frame: 60 months ]
    Health-related quality-of-life, measured using EuroQol (EQ-5D-5L) questionnaire, Score 0-100
  • Urinary side effects [ Time Frame: 60 months ]
    Urinary side effects, measured using the IPSS questionnaire, Score 0-35
  • Urinary side effects [ Time Frame: 60 months ]
    Urinary side effects, measured using the EPIC-Urinary domain questionnaire, Score 0-34
  • Sexual side effects [ Time Frame: 60 months ]
    Sexual side effects, measured using the IIEF15 questionnaire, Score 0-75.
  • Effect on quality of life [ Time Frame: 60 months ]
    Effect on quality of life, measured using the EPIC - 26 questionnaire, Score 0-79
  • Impact of participants' overall health-related quality assessed by validated patient reported outcomes measures [ Time Frame: 60 months ]
    To observe the impact of participants' overall health-related quality- of- life as well as adverse events and impact on genito-urinary and rectal functional status using validated patient reported outcomes measures (International Index of Erectile Function-15, EPIC-26, EPIC Urinary domain, International Prostate Symptom Score and CTCAEv4.0 bowel domain). Further analysis to be performed using qualitative interview datasets in a multi-methods analysis.
  • Comparison of predictive value of different MRI scoring systems against histological outcomes. [ Time Frame: 60 months ]
    To compare the predictive value of the PI-RADS and/or Likert scoring system against histological outcomes in patients treated with localised, clinically significant prostate cancer over at least 5 years.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer
Official Title  ICMJE Imperial Prostate 4: Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
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
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Non-metastatic Prostate Cancer
  • Prostate Adenocarcinoma
Intervention  ICMJE
  • Procedure: Radical therapy (radiotherapy or prostatectomy [radiotherapy can be external beam or brachytherapy]
    Radical therapy (radiotherapy or prostatectomy [radiotherapy can be external beam or brachytherapy]
    Other Names:
    • radiotherapy
    • prostatectomy
    • external beam radiotherapy
    • brachytherapy
  • Procedure: Focal therapy
    Focal therapy (high intensity focused ultrasound or cryotherapy)
    Other Names:
    • high intensity focused ultrasound
    • cryotherapy
    • HIFU
  • Procedure: Focal therapy after Finasteride 5Mg tablets for 12 weeks
    finasteride 5mg tablets 12 weeks prior to focal therapy
    Other Name: Neoadjuvant
  • Procedure: Focal therapy after Bicalutamide 50Mg tablets for 12 weeks
    Bicalutamide 50mg per day - 12 weeks prior to focal therapy
    Other Name: Neoadjuvant
Study Arms  ICMJE
  • Experimental: CHRONOS A - Arm 1 (Control)
    Radical therapy (radiotherapy or prostatectomy [radiotherapy can be external beam or brachytherapy]). In patients undergoing radiotherapy a maximum of 6-months neo-adjuvant hormonal therapy will be allowed. In patients undergoing radical prostatectomy, cytoreduction of maximum 6 months with medication will be permissible, provided this is part of local practice.
    Intervention: Procedure: Radical therapy (radiotherapy or prostatectomy [radiotherapy can be external beam or brachytherapy]
  • Experimental: CHRONOS A - Arm 2 (Intervention)
    Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy as per physician and centre choice). A second focal therapy session in-field, or a first focal therapy session to an out-of-field progressive or de novo lesion will be allowed as part of the focal therapy intervention.
    Intervention: Procedure: Focal therapy
  • Experimental: CHRONOS B - Arm 3 (Control)
    Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy as per physician and centre choice). A second treatment in-field, or a first focal ablation to an out-of-field progressive or de novo lesion will be allowed but will be regarded as failure events for the purpose of CHRONOS-B.
    Intervention: Procedure: Radical therapy (radiotherapy or prostatectomy [radiotherapy can be external beam or brachytherapy]
  • Experimental: CHRONOS B - Arm 4 (Intervention):
    Neoadjuvant finasteride 5mg once daily for a minimum of 12 weeks followed by focal therapy (as per CHRONOS B control arm).
    Intervention: Procedure: Focal therapy after Finasteride 5Mg tablets for 12 weeks
  • Experimental: CHRONOS B - Arm 5 (Intervention)
    Neoadjuvant bicalutamide 50mg once daily therapy for a minimum of 12 weeks followed by focal therapy (as per control arm).
    Intervention: Procedure: Focal therapy after Bicalutamide 50Mg tablets for 12 weeks
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 7, 2019)
2450
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2027
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hashim Ahmed 0203 311 1673 hashim.ahmed@imperial.ac.uk
Contact: Thiagarajah Sasikaran, PhD 0207 594 6017 t.sasikaran@imperial.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04049747
Other Study ID Numbers  ICMJE 19CX5006
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Imperial College London
Study Sponsor  ICMJE Imperial College London
Collaborators  ICMJE
  • Prostate Cancer UK
  • Imperial Clinical Trials Unit (ICTU)
Investigators  ICMJE
Principal Investigator: Hashim Ahmed Imperial College London
PRS Account Imperial College London
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP