Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy

Study Overview
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Brief Summary
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The overall aim of this trial, which is called STAMPEDE, is to assess novel approaches for the treatment of men with prostate cancer who are starting long-term ADT for the first time, termed hormone-naïve prostate cancer. This trial aims to see if we can improve the way in which prostate cancer is currently managed, either by adding new treatments to the standard approach or by modifying the type of hormone therapy aiming to improve quality-of-life by reducing the side effects of treatment. Each new treatment approach is compared against a control arm receiving the current standard treatments. We aim to identify treatment strategies that enable men to live longer, or as long but with an improved quality-of-life, as well as offering value for money for the health service. Since opening to accrual in Oct-2005, the trial has tested many ways of treating prostate cancer and some results are now already known. More than 10,000 men will join the trial with answers becoming available throughout the trial. New patients joining the trial from Protocol version 17.0 onwards (activated in December 2018) may be eligible to join one of two treatment comparisons, metformin (treatment group K; the metformin comparison) and transdermal oestradiol (treatment group L; the transdermal oestradiol comparison). A computer program will be used to allocate which treatment each participant receives, using a chance process. Summary of the research arms in STAMPEDE trial platform Summary of research treatment groups currently open to recruitment (June 2017) Metformin (Arm K): This anti-diabetic medication is proposed to have both anti-cancer effects and may help prevent the adverse metabolic effects of long-term ADT. STAMPEDE will investigate whether adding metformin to the current standard-of-care for non-diabetic men can improve all-cause survival. Transdermal oestradiol (Arm L): This is an alternative form of hormone treatment which has been shown to suppress testosterone as effectively as standard ADT and avoid some of the side-effects. It may also help to avoid the adverse metabolic effects and fatigue and therefore improve overall quality of life compared with standard forms of ADT. STAMPEDE will investigate whether transdermal oestradiol can treat the cancer as well as current standard forms of ADT. Control group (Arm A): Patients allocated to this group receive the current standard-of-care ADT +/- RT +/- docetaxel.

Detailed Description
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STAMPEDE (also known as MRC PR08) is a multi-arm multi-stage (MAMS) randomised controlled trial recruiting in the UK and Switzerland. It aims to evaluate multiple therapeutic strategies in the management of high-risk locally advanced and metastatic hormone-naïve prostate cancer. Each novel treatment strategy is compared against a single, contemporaneous control arm. When the trial originally opened in 2005 there were 6 research arms enabling 5 randomised comparisons. Each comparison is evaluated in stages with pre-planned interim analyses after which recruitment may be halted should the experimental treatment fail to reach a hurdle of activity. Patient data from all arms and all stages are, however, included in the final analyses of the primary outcome measure, even if the investigational arm did not proceed to the final stage. Providing sufficient activity is demonstrated, recruitment continues to the final stage and then an assessment of efficacy is determined based on the primary outcome of overall survival. Patient data from all arms and all stages are included in the final analyses of the primary outcome measure, even if the investigational arm did not proceed to the final stage. The original comparisons which have all now been reported, evaluated a bisphosphonate (zoledronic acid), a cytotoxic chemotherapeutic agent (docetaxel) and a cyclooxygenase (Cox 2) inhibitor (celecoxib), as single agents or combinations. Since the start of the trial, a number of new research arms have been added to STAMPEDE over time to evaluate: abiraterone, a steroid synthesis inhibitor; prostate radiotherapy for patients with newly diagnosed metastatic disease; enzalutamide, an inhibitor of androgen receptor signalling, given with abiraterone; and metformin, an anti-diabetic medication and transdermal oestradiol, to be given as an alternative form of ADT. Objectives: Primary To compare the safety and efficacy of novel therapeutic strategies against the current standard-of-care for men with high-risk locally advanced or metastatic prostate cancer starting long-term ADT for the first time. Outline: This is a randomised, controlled, multi-centre MAMS trial platform. Patients are current randomised to 1 of 3 arms: control group (arm A), metformin treatment group (arm K) and transdermal oestradiol (Arm L). The other arms are all closed to recruitment with results known for all the original comparisons and awaited for others added since the trial commenced. Patient population: STAMPEDE recruits both men with high-risk locally advanced prostate cancer and men with metastatic prostate cancer, all of whom must be starting long-term ADT for the first time. Patients who received previous radical treatment and are now relapsing with high-risk features are also eligible. Follow-up: All patients are follow-up life long Sub-studies: There are several translational sub-studies ongoing as part of STAMPEDE. Participation is optional. These currently include several translational sub-studies involving sample collection: saliva collection for germline DNA analysis, sequential circulating tumour DNA analysis and FFPE tumour block retrieval for DNA and RNA analysis. Other sub-studies include a QOL sub-study and an imaging sub-study.

Official Title
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STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Celecoxib
* Drug: Docetaxel
* Drug: Prednisolone
* Drug: ADT
* Drug: Zoledronic Acid
* Drug: Abiraterone
* Radiation: Radiotherapy to the prostate
* Drug: Enzalutamide
* Drug: Metformin
* Drug: Transdermal Oestradiol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants must fulfil all the criteria in one of the following three categories. Additionally, all patients must fulfil the criteria in Section 4. High-Risk Newly-Diagnosed Non-Metastatic Node-Negative (N0/Nx) Disease Both: • At least two of: T category T3/4, PSA≥40ng/ml or Gleason sum score 8-10 • Intention to treat with radical radiotherapy (unless there is a contra-indication) OR Newly-Diagnosed Metastatic Or Node-Positive Disease At least one of: Stage Tany N+ M0 Stage Tany Nany M+ OR Previously Radically Treated, Now Relapsing (Prior Radical Surgery And/or Radiotherapy) At least one of: • PSA ≥4ng/ml and rising with doubling time less than 6 months • PSA ≥20ng/ml • N+ • M+ AND General Inclusion Criteria Required For All Participants Histologically confirmed prostate adenocarcinoma Intention to treat with long-term androgen deprivation therapy Fit for all protocol treatment and follow up, WHO performance status 0-2 Have completed the appropriate investigations prior to randomisation Adequate haematological function: neutrophil count ≥1.5x109/l and platelets ≥100x109/l Adequate renal function, defined as GFR ≥30ml/min/1.73m2 Written informed consent Willing and expected to comply with follow up schedule Using effective contraceptive method if applicable Medical contraindications to the trial medications are given in Section 6 For WHO performance status definitions see Appendix A 5. General Exclusion Criteria Patients must not fulfil any of the criteria below: Prior systemic therapy for locally-advanced or metastatic prostate cancer (1) (except as listed in the protocol section 4.3) Prior exposure to hormone therapy for a duration of > 12 months, or prior exposure completing < 12 months before randomisation (see section 4.3.1 for permitted prior exposure details) Metastatic brain disease or leptomeningeal disease Abnormal liver functions consisting of any of the following: • Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert's disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN - site must indicate at randomisation whether one or both tests are performed at site. Where both results are available both must confirm eligibility. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment Any surgical wound (e.g. TURP) which in the judgement of the responsible clinician may interfere with or be exacerbated by protocol treatment Participant with significant cardiovascular disease, including: • Severe/unstable angina • Myocardial infarction less than 6 months prior to randomisation • Arterial thrombotic events less than 6 months prior to randomisation • Clinically significant cardiac failure requiring treatment, defined as New York Heart Association (NYHA) class II or above (1) • Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 6 months prior to randomisation Any other significant cardiovascular disease that in the investigator's opinion means the participant is unfit for any of the study treatments. Excluding participants receiving docetaxel as part of SOC NYHA classifications can be found in Appendix A 6. Comparison-specific eligibility criteria In addition to the general inclusion and exclusion criteria, the following comparison-specific eligibility criteria apply. For Randomisation to the Metformin Comparison Please note from protocol v20 only patients willing to participate in the metabolic sub study should be randomised to the metformin comparison. The sub study will be conducted in a limited number of sites, see section 4.7.4 for further information. In addition to the general inclusion and general exclusion criteria the following comparison-specific inclusion criteria must be met to be eligible for randomisation to the metformin comparison: • HbA1c <48mmol/mol (equivalent to <6.5%) (1) • Adequate renal function, defined as GFR ≥45ml/min/1.73m (except for Switzerland (2)) • No history of lactic acidosis or pre-disposing conditions Not current or previous treatment with metformin No contra-indications to metformin No current or previous medication for treatment of diabetes Willingness to join the metabolic sub study The method used to determine glomerular filtration rate may vary according to local practice. Equations that either estimate glomerular filtration rate (eGFR) or creatinine clearance (CrCl) may be used and the same threshold value applies. Where possible, HbA1c should be performed prior to commencing SOC docetaxel to reduce the likelihood of corticosteroid-related hyperglycaemia impacting on eligibility. All participants with abnormal baseline HbA1c (i.e. 6.5% or higher) should be informed and referred to their GP for further management. (2) Except Switzerland, please refer to SAKK appendix for local guidance For Randomisation To The Transdermal Oestradiol Comparison In addition to the general inclusion and exclusion criteria, participants fulfilling all of the following are eligible for the transdermal oestradiol comparison: • ≤8 weeks of anti-androgen (AR-antagonists) use • Maximum of 1 dose of monthly or 4-weekly LHRH agonist/antagonist • No prior LHRH agonist injection with a stated duration of effect greater than 1 month • ≤12 weeks since first dose of any hormone therapy • Not had a bilateral orchidectomy • No use of cyproterone acetate (36) prior to randomisation • No known porphyria No known history of deep vein thrombosis or pulmonary embolism confirmed radiologically No known thrombophilic disorder (e.g. Protein C, Protein S, antithrombin deficiency) Not yet started SOC abiraterone, enzalutamide or apalutamide

Ages Eligible for Study
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Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-arm Multi-Stage
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Standard of Care<br>Androgen Deprivation Therapy [ADT] (plus Radiotherapy for newly-diagnosed non-metastatic disease, plus or minus Docetaxel, plus or minus Abiraterone)[Control] | Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;|
| Experimental: Arm B: Zoledronic Acid<br>(ADT + zoledronic acid) NO LONGER RECRUITING | Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Zoledronic Acid<br> <br> * Other names: Zometa;|
| Experimental: Arm C: Docetaxel<br>(ADT + docetaxel + prednisolone) NO LONGER RECRUITING | Drug: Docetaxel<br> <br> * Other names: Taxotere;Drug: Prednisolone<br> <br> * Other names: Prednisone;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;|
| Experimental: Arm D: Celecoxib<br>(ADT + celecoxib) NO LONGER RECRUITING | Drug: Celecoxib<br> <br> * Other names: Celebrex;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;|
| Experimental: Arm E: Zoledronic Acid & Docetaxel<br>(ADT + zoledronic acid + docetaxel + prednisolone) NO LONGER RECRUITING | Drug: Docetaxel<br> <br> * Other names: Taxotere;Drug: Prednisolone<br> <br> * Other names: Prednisone;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Zoledronic Acid<br> <br> * Other names: Zometa;|
| Experimental: Arm F: Zoledronic Acid & Celecoxib<br>(ADT + zoledronic acid + celecoxib) NO LONGER RECRUITING | Drug: Celecoxib<br> <br> * Other names: Celebrex;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Zoledronic Acid<br> <br> * Other names: Zometa;|
| Experimental: Arm G: Abiraterone<br>(ADT + abiraterone acetate + prednisolone) NO LONGER RECRUITING | Drug: Prednisolone<br> <br> * Other names: Prednisone;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Abiraterone<br> <br> * Other names: Zytiga;|
| Experimental: Arm H: M1 RT<br>(ADT + radiotherapy to the prostate) NO LONGER RECRUITING | Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Radiation: Radiotherapy to the prostate<br> <br> * Other names: RT;|
| Experimental: Arm J: Abiraterone * Enzalutamide<br>(ADT + abiraterone + enzalutamide + Prednisolone) NO LONGER RECRUITING | Drug: Prednisolone<br> <br> * Other names: Prednisone;Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Abiraterone<br> <br> * Other names: Zytiga;Drug: Enzalutamide<br> <br> * Other names: Xtandi;|
| Experimental: Arm K: Metformin<br>(ADT + Metformin) RECRUITING IN SELECTED SITES | Drug: ADT<br> <br> * Other names: Androgen Deprivation Therapy;Drug: Metformin<br> <br> * Other names: Metformin Hydrochloride;|
| Experimental: Arm L: tE2<br>(Transdermal oestradiol) RECRUITING | Drug: Transdermal Oestradiol<br> <br> * Other names: Progynova TS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time to mortality | 1:Not applicable | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free survival | Report of time from initiation of treatment to the first progression event of each patient | 1:Not applicable | 
| Cost effectiveness by EuroQol | Reporting the comparison of costs associated with the additional treatments provided and the survival gain attributed to the additional treatments, to SOC alone. | 1:Not applicable | 
| Quality of life (QOL) by EORTC QOL Questionnaire C30 and prostate specific 25-item | Determination of changes in quality of life with interventions | 1:Not applicable | 
| Number of participants with treatment-related side effects as assessed by CTCAE v4.0 | Reporting the incidence, type and severity of side effects within the trial population. CTCAE v4.0 will be used to classify the events names and severity. | 1:Not applicable | 
| Skeletal related events | Reporting the incidence and types of skeletal related events | 1:Not applicable | 
| Biochemical failure | For the purposes of the STAMPEDE trial, a unique threshold PSA value for biochemical failure is calculated for each patient, referred to as the PSA progression value. A. If PSA nadir in the 24 weeks following randomisation is more than 4ng/ml and more than 50% of the pre-treatment PSA level - immediate treatment failure. B. If PSA nadir in the 24 weeks following randomisation is less than or equal to 50% of the pre-treatment PSA level but remains above 4ng/ml - treatment failure will be defined as a rise of 50% above the nadir level. C. If PSA nadir in the 24 weeks following randomisation is less than or equal to 4ng/ml - treatment failure will be defined as at least 50% rise above the nadir value and also above 4ng/ml. | 1:Not applicable | 
| Progression-free survival | Reporting the incidence of mortality without a progression event | 1:Not applicable | 
| Lymph node progression | Reporting the incidence and severity of lymph node events | 1:Not applicable | 
| Distant metastases | Reporting the incidence and severity of distant metastatic events | 1:Not applicable | 
| Treatment for progression | Identifying and reporting the treatments used in second line treatment. Incidence and types of treatments. | 1:Not applicable | 
| Disease-specific survival | Reporting the mortality attributed to Prostate Cancer | 1:Not applicable | 
| Non-prostate cancer death | Reporting the mortality not attributed to Prostate Cancer | 1:Not applicable | 
| Metabolic effects | Reporting the incidence and severity of effects on metabolic systems | 1:Not applicable | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III Prostate Cancer, Stage IV Prostate Cancer, Recurrent Prostate Cancer, Adenocarcinoma of the prostate