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

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ClinicalTrials.gov Identifier: NCT00268476
Recruitment Status : Recruiting
First Posted : December 22, 2005
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
Medical Research Council

December 20, 2005
December 22, 2005
March 29, 2018
July 8, 2005
September 2024   (Final data collection date for primary outcome measure)
Overall survival [ Time Frame: 1:Not applicable ]
Time to mortality
Not Provided
Complete list of historical versions of study NCT00268476 on ClinicalTrials.gov Archive Site
  • Failure-free survival [ Time Frame: 1:Not applicable ]
    Time to progression event
  • Cost effectiveness by EuroQol [ Time Frame: 1:Not applicable ]
    Comparison of additional costs and survival gain to SOC.
  • Quality of life (QOL) by EORTC QOL Questionnaire C30 and prostate specific 25-item [ Time Frame: 1:Not applicable ]
    Determination of changes in quality of life with interventions
  • Toxicity [ Time Frame: 1:Not applicable ]
    Incidence and types of IMP toxicities
  • Skeletal related events [ Time Frame: 1:Not applicable ]
    Incidence and types of skeletal related events
  • Biochemical failure [ Time Frame: 1:Not applicable ]

    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.

  • Progression-free survival [ Time Frame: 1:Not applicable ]
    Incidence of mortality without a progression event
  • Lymph node progression [ Time Frame: 1:Not applicable ]
    Incidence and severity of lymph node events
  • Distant metastases [ Time Frame: 1:Not applicable ]
    Incidence and severity of distant metastatic events
  • Treatment for progression [ Time Frame: 1:Not applicable ]
    Identifying the treatments used in second line treatment
  • Disease-specific survival [ Time Frame: 1:Not applicable ]
    Mortality attributed to Prostate Cancer
  • Non-prostate cancer death [ Time Frame: 1:Not applicable ]
    Mortality not attributed to Prostate Cancer
  • Metabolic effects [ Time Frame: 1:Not applicable ]
    Incidence and severity of effects on metabolic systems
Not Provided
Not Provided
Not Provided
 
Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy
STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial

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)

  1. 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.
  2. 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.
  3. Control group (Arm A): Patients allocated to this group receive the current standard-of-care ADT +/- RT +/- docetaxel.

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Multi-arm Multi-Stage
Masking: None (Open Label)
Primary Purpose: Treatment
Prostate Cancer
  • Drug: Celecoxib
    Other Name: Celebrex
  • Drug: Docetaxel
    Other Name: Taxotere
  • Drug: Prednisolone
    Other Name: Prednisone
  • Drug: ADT
    Other Name: Androgen Deprivation Therapy
  • Drug: Zoledronic Acid
    Other Name: Zometa
  • Drug: Abiraterone
    Other Name: Zytiga
  • Radiation: Radiotherapy to the prostate
    Other Name: RT
  • Drug: Enzalutamide
    Other Name: Xtandi
  • Drug: Metformin
    Other Name: Metformin Hydrochloride
  • Drug: Transdermal Oestradiol
    Other Name: Progynova TS
  • Active Comparator: Arm A: Standard of Care
    Androgen Deprivation Therapy [ADT] (plus Radiotherapy for newly-diagnosed non-metastatic disease, plus or minus Docetaxel, plus or minus Abiraterone)[Control]
    Intervention: Drug: ADT
  • Experimental: Arm B: Zoledronic Acid
    (ADT + zoledronic acid) NO LONGER RECRUITING
    Interventions:
    • Drug: ADT
    • Drug: Zoledronic Acid
  • Experimental: Arm C: Docetaxel
    (ADT + docetaxel + prednisolone) NO LONGER RECRUITING
    Interventions:
    • Drug: Docetaxel
    • Drug: Prednisolone
    • Drug: ADT
  • Experimental: Arm D: Celecoxib
    (ADT + celecoxib) NO LONGER RECRUITING
    Interventions:
    • Drug: Celecoxib
    • Drug: ADT
  • Experimental: Arm E: Zoledronic Acid & Docetaxel
    (ADT + zoledronic acid + docetaxel + prednisolone) NO LONGER RECRUITING
    Interventions:
    • Drug: Docetaxel
    • Drug: Prednisolone
    • Drug: ADT
    • Drug: Zoledronic Acid
  • Experimental: Arm F: Zoledronic Acid & Celecoxib
    (ADT + zoledronic acid + celecoxib) NO LONGER RECRUITING
    Interventions:
    • Drug: Celecoxib
    • Drug: ADT
    • Drug: Zoledronic Acid
  • Experimental: Arm G: Abiraterone
    (ADT + abiraterone acetate + prednisolone) NO LONGER RECRUITING
    Interventions:
    • Drug: Prednisolone
    • Drug: ADT
    • Drug: Abiraterone
  • Experimental: Arm H: M1 RT
    (ADT + radiotherapy to the prostate) NO LONGER RECRUITING
    Interventions:
    • Drug: ADT
    • Radiation: Radiotherapy to the prostate
  • Experimental: Arm J: Abiraterone * Enzalutamide
    (ADT + abiraterone + enzalutamide + Prednisolone) NO LONGER RECRUITING
    Interventions:
    • Drug: Prednisolone
    • Drug: ADT
    • Drug: Abiraterone
    • Drug: Enzalutamide
  • Experimental: Arm K: Metformin
    (ADT + Metformin) RECRUITING
    Interventions:
    • Drug: ADT
    • Drug: Metformin
  • Experimental: Arm L: tE2
    (Transdermal oestradiol) RECRUITING
    Intervention: Drug: Transdermal Oestradiol

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
11200
Not Provided
September 2024
September 2024   (Final data collection date for primary outcome measure)

Inclusion Criteria Participants must fulfil both of the criteria in Section 1 or at least one criterion in Section 2 or at least one criterion in Section 3 of the protocol. Additionally, all patients must fulfil the criteria in Section 4.

  1. High-Risk Newly-Diagnosed Non-Metastatic Node-Negative 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; exemption can be sought in advance of consent, after discussion with CTU)

    OR

  2. Newly-Diagnosed Metastatic Or Node-Positive Disease

    At least one of:

    •Stage Tany N+ M0

    •Stage Tany Nany M+

    OR

  3. 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

  4. For All Patients
  1. Histologically confirmed prostate adenocarcinoma
  2. Intention to treat with long-term androgen deprivation therapy
  3. Treating clinician and patient should have decided if docetaxel is to be part of the standard-of-care prior to randomisation
  4. Fit for all protocol treatment1 and follow-up, WHO performance status 0-22
  5. Have completed the appropriate investigations prior to randomisation
  6. Adequate haematological function: neutrophil count >1.5x109/l and platelets >100x109/l
  7. Adequate renal function, defined as GFR >30ml/min/1.73m2
  8. Serum potassium ≥3.5mmol/L
  9. Written informed consent
  10. Willing and expected to comply with follow-up schedule
  11. Using effective contraceptive method if applicable
  1. Medical contraindications to the trial medications are given in Section 6
  2. For WHO performance status definitions see Appendix A

Exclusion Criteria

Patients must not fulfil any of the criteria, below.

  1. Prior systemic therapy for locally-advanced or metastatic prostate cancer except as listed above
  2. Metastatic brain disease or leptomeningeal disease
  3. 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
  4. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment
  5. Any surgery (e.g. TURP) performed within the past 4 weeks
  6. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include:

    •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 (NYHA II-IV)3

    •Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 6 months prior to randomisation

    •Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160mmHg or diastolic BP greater or equal than 95mmHg5

  7. Prior chemotherapy for prostate cancer (excluding patients receiving docetaxel as part of the new SOC)
  8. Prior exposure to long-term hormone therapy before randomisation
  9. Prior exposure to systemic treatment for prostate cancer (excluding hormone therapy) e.g. abiraterone and enzalutamide.

3 NYHA classifications can be found in Appendix A

5 Based on representative values, as judged by the investigator

For Randomisation to the "Metformin Comparison"

Patients with known diabetes mellitus are not eligible for randomisation to the "metformin comparison". All non-diabetic patients require an HbA1c to be performed prior to randomisation (ideal timeline: within 8 weeks prior to randomisation), to confirm their non-diabetic status.

In addition, an assessment of renal function is required to determine glomerular filtration rate (GFR). The method used to determine glomerular filtration rate may vary according local practice. Equations that either estimate glomerular filtration rate (eGFR) or creatinine clearance (CrCl) may be used and the same threshold value applies. In summary, additional inclusion criteria specifically for the "metformin comparison" are

•HbA1c <48mmol/mol (equivalent to <6.5%)*

•Adequate renal function, defined as GFR ≥45ml/min/1.73m2

  • No history of lactic acidosis or pre-disposing conditions
  • Not current or previous treatment with metformin
  • No contra-indications to metformin

    • Except Switzerland, please refer to SAKK appendix for local guidance

Note that if the patient is known to be diabetic or the patient is found to have diabetes mellitus (i.e. HbA1c is 6.5% or higher) following screening, the patient is only eligible for randomisation if they meet all of the selection criteria for the "transdermal oestradiol comparison" (randomisation between Arms A and L only) All patients with abnormal baseline HbA1c (i.e. 6.0% or higher) should be informed and referred to their GP for further management.

Where possible, the screening bloods, including HbA1c, should be performed prior to commencing SOC docetaxel. This is to reduce the likelihood of corticosteroid-related hyperglycaemia impacting on eligibility for the "metformin comparison".

For Randomisation To The "Transdermal Oestradiol Comparison"

Patients who have any of the following are not eligible for the "transdermal oestradiol comparison":

•>8 weeks of anti-androgen use

•>1 dose of monthly or 4 weekly LHRH agonist/antagonist

  • Prior LHRH agonist injection with a stated duration of effect greater than 1 month •>12 weeks since first dose of any hormone therapy
  • Bilateral orchidectomy
  • Cyproterone acetate started prior to randomisation
  • Known porphyria
  • Any history of deep vein thrombosis or pulmonary embolism confirmed radiologically
  • Known thrombophilic disorder (e.g. Protein C, protein S, antithrombin deficiency)

Note that patients unsuitable for the "transdermal oestradiol comparison" will only be eligible for randomisation if they meet all of the selection criteria for the "metformin comparison" and therefore may be allocated to control (arm A) or metformin (arm K) only.

Sexes Eligible for Study: Male
up to 120 Years   (Child, Adult, Senior)
No
Contact: STAMPEDE Trial Team +44 (0)20 7670 4700 mrcctu.stampede@ucl.ac.uk
Switzerland,   United Kingdom
 
 
NCT00268476
CDR0000455008
MRC-STAMPEDE ( Other Identifier: MRC )
EU-205102 ( Other Identifier: EU )
PR08 ( Other Identifier: MRC CTU at UCL )
ISRCTN78818544 ( Registry Identifier: ISRCTN )
2004-000193-31 ( EudraCT Number )
Yes
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Medical Research Council
Medical Research Council
Not Provided
Study Chair: Nicholas D. James, MD University Hospital Birmingham
Medical Research Council
March 2018

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