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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 (STAMPEDE)

This study is currently recruiting participants.
Verified September 2017 by Medical Research Council
Sponsor:
ClinicalTrials.gov Identifier:
NCT00268476
First Posted: December 22, 2005
Last Update Posted: September 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Medical Research Council
December 20, 2005
December 22, 2005
September 25, 2017
September 2005
September 2024   (Final data collection date for primary outcome measure)
Overall survival [ Time Frame: 1:Not applicable ]
Not Provided
Complete list of historical versions of study NCT00268476 on ClinicalTrials.gov Archive Site
  • Failure-free survival [ Time Frame: 1:Not applicable ]
  • Cost effectiveness by EuroQol [ Time Frame: 1:Not applicable ]
  • Quality of life (QOL) by EORTC QOL Questionnaire C30 and prostate specific 25-item [ Time Frame: 1:Not applicable ]
  • Toxicity [ Time Frame: 1:Not applicable ]
  • Skeletal related events [ Time Frame: 1:Not applicable ]
  • Biochemical failure [ Time Frame: 1:Not applicable ]
  • Progression-free survival [ Time Frame: 1:Not applicable ]
  • Lymph node progression [ Time Frame: 1:Not applicable ]
  • Distant metastases [ Time Frame: 1:Not applicable ]
  • Treatment for progression [ Time Frame: 1:Not applicable ]
  • Disease-specific survival [ Time Frame: 1:Not applicable ]
  • Non-prostate cancer death [ Time Frame: 1:Not applicable ]
  • Metabolic effects [ Time Frame: 1:Not applicable ]
Not Provided
Not Provided
Not Provided
 
STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial
STAMPEDE: Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy - Androgen Suppression-Based Therapy Alone or Combined With Zoledronic Acid, Docetaxel, Prednisolone, Celecoxib, Abiraterone, Enzalutamide and/or Radiotherapy, Metformin and Transdermal Oestradiol in Treating Patients With Locally Advanced or Metastatic Prostate Cancer

Prostate cancers need the male hormone testosterone to grow. Hormone treatments work by stopping testosterone from reaching prostate cancer cells. There are different types of hormone treatments but the most common are injections or implants that work by stopping the testicles making testosterone. Some men will have an operation to remove a part or all of the testicles instead. This type of treatment is called hormone treatment or androgen deprivation therapy (ADT) and it is part of the current standard approach to the treatment of locally advanced or metastatic prostate cancer. In addition, radiotherapy to the prostate and or docetaxel chemotherapy may be recommended as part of the current standard-of-care.

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 16.0 onwards (activated in June 2017) 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
Masking: None (Open Label)
Primary Purpose: Treatment
Prostate Cancer
  • Drug: Celecoxib
  • Drug: Docetaxel
  • Drug: Prednisolone
  • Drug: ADT
  • Drug: Zoledronic Acid
  • Drug: Abiraterone
  • Procedure: Orchiectomy
  • Radiation: Radiotherapy to the prostate
  • Drug: Enzalutamide
  • Drug: Metformin
  • Drug: Transdermal Oestradiol
  • Active Comparator: Arm A Androgen Deprivation Therapy [ADT]
    (plus Radiotherapy for newly-diagnosed non-metastatic disease)[Control]
    Interventions:
    • Drug: ADT
    • Procedure: Orchiectomy
  • Experimental: Arm B (ADT + zoledronic acid)
    NO LONGER RECRUITING
    Interventions:
    • Drug: ADT
    • Drug: Zoledronic Acid
    • Procedure: Orchiectomy
  • Experimental: Arm C (ADT + docetaxel + prednisolone)
    NO LONGER RECRUITING
    Interventions:
    • Drug: Docetaxel
    • Drug: Prednisolone
    • Drug: ADT
    • Procedure: Orchiectomy
  • Experimental: Arm D (ADT + celecoxib)
    NO LONGER RECRUITING
    Interventions:
    • Drug: Docetaxel
    • Drug: Prednisolone
    • Drug: ADT
    • Drug: Zoledronic Acid
    • Procedure: Orchiectomy
  • Experimental: Arm E (ADT + zoledronic acid + docetaxel + prednisolone)
    NO LONGER RECRUITING
    Interventions:
    • Drug: ADT
    • Drug: Abiraterone
    • Procedure: Orchiectomy
  • Experimental: Arm F (ADT + zoledronic acid + celecoxib)
    NO LONGER RECRUITING
    Interventions:
    • Drug: Celecoxib
    • Drug: ADT
    • Procedure: Orchiectomy
  • Experimental: Arm G (ADT + abiraterone)
    NO LONGER RECRUITING
    Interventions:
    • Drug: Celecoxib
    • Drug: ADT
    • Procedure: Orchiectomy
  • Experimental: Arm H (ADT + radiotherapy to the prostate)
    NO LONGER RECRUITING
    Interventions:
    • Drug: ADT
    • Procedure: Orchiectomy
    • Radiation: Radiotherapy to the prostate
  • Experimental: Arm J (ADT + abiraterone + enzalutamide)
    NO LONGER RECRUITING
    Interventions:
    • Drug: Prednisolone
    • Drug: ADT
    • Drug: Abiraterone
    • Drug: Enzalutamide
  • Experimental: Arm K (ADT+/- prostate RT +/- docetaxel + Metformin)
    RECRUITING
    Intervention: Drug: Metformin
  • Experimental: Arm L (Transdermal oestradiol +/- RT +/- docetaxel)
    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
8100
September 2024
September 2024   (Final data collection date for primary outcome measure)

GENERAL INCLUSION CRITERIA

To be eligible participants must fulfil the criteria within one of the broad disease categories below:

  1. High-Risk Newly-Diagnosed Non-Metastatic Node-Negative Disease (N0M0, with at least two of: T category T3/4, PSA≥40ng/ml or Gleason sum score 8-10 and intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can be sought in advance of consent, after discussion with CTU)
  2. Newly-Diagnosed Non-Metastatic Node-Positive Disease (T any N+ M0)
  3. Newly-Diagnosed metastatic (T any N any M+)
  4. Previously Radically Treated, Now Relapsing (Prior Radical Surgery And/Or Radiotherapy): with at least one of: M1, N+, PSA ≥4ng/ml and rising with doubling time less than 6 months; PSA ≥20ng/ml)

In addition all patients must meet the following criteria:

I. Histologically confirmed prostate adenocarcinoma

II. Intention to treat with long-term androgen deprivation therapy

III. Treating clinician and patient should have decided if docetaxel is to be part of the standard-of-care prior to randomisation

IV. Fit for all protocol treatment and follow-up, WHO performance status 0-2

V. Have completed the appropriate investigations prior to randomisation

VI. Adequate haematological function: neutrophil count >1.5x109 /l and platelets >100x109 /l

VII. Adequate renal function, defined as GFR >30ml/min/1.73m 2

VIII. Serum potassium ≥3.5mmol/L

IX. Written informed consent

X. Willing and expected to comply with follow-up schedule

XI. Using effective contraceptive method if applicable

Patients must not fulfil any of the following general exclusion criteria

I. Prior systemic therapy for locally-advanced or metastatic prostate cancer (except previously radically treated, now relapsing patients (prior radical surgery and/ or radiotherapy)

II. Metastatic brain disease or leptomeningeal disease

III. 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

IV. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment

V. Any surgery (e.g. TURP) performed within the past 4 weeks

VI. 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 • 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 95mmHg (based on representative values as judged by the investigator)

VII. Prior chemotherapy for prostate cancer (excluding patients receiving docetaxel as part of the new SOC)

VIII. Prior exposure to long-term hormone therapy before randomisation. (Any patients now presenting with relapsed disease, previously treated with adjuvant or neo adjuvant hormone therapy alongside their radical surgery or radiotherapy, must have completed that period of hormone therapy at least 12 months before joining STAMPEDE and it must have been no longer than 12 months in duration).

IX. Prior exposure to systemic treatment for prostate cancer (excluding hormone therapy) e.g. abiraterone and enzalutamide.

Comparison-Specific Selection Criteria

To be eligible for randomisation to the "metformin comparison" patients must fulfil the following criteria:

  • 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

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, prostein S, antithrombin deficiency)
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
EU-205102
MRC-PR08
ISRCTN78818544
EUDRACT-2004-000193-31
Yes
Not Provided
Not Provided
Medical Research Council
Medical Research Council
Not Provided
Study Chair: Nicholas D. James, MD University Hospital Birmingham
Medical Research Council
September 2017

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