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Systemic Therapy in Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy
ISRCTN ISRCTN78818544
DOI 10.1186/ISRCTN78818544
ClinicalTrials.gov identifier NCT00268476
EudraCT number 2004-000193-31
Public title Systemic Therapy in Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy
Scientific title
Acronym STAMPEDE
Serial number at source N/A
Study hypothesis Currenty study hypothesis as of 23/01/2013:
Recruitment to the celecoxib arms (D and F) is now closed. An additional arm containing abiraterone was added in protocol version 8.0. A further comparison arm involving prostate radiotherapy for patients with metastatic disease is added in the current protocol version 9.0. The trial has multiple arms; the control arm of the trial is androgen deprivation therapy (ADT) only, achieved through the use of luteinising hormone releasing hormone (LHRH) analogues or LHRH antagonists, or bilateral orchidectomy according to local practice.

Added as of 11/09/2008:
Prostate cancer accounts for around one fifth of all cancers among men. In the UK there are around 25,000 new cases of prostate cancer each year, and around 10,000 deaths. Most men are given hormone therapy if their prostate cancer has spread (metastasised), or if the cancer is very likely to spread. This usually stops the tumour from growing for a while. But in most cases over time the tumour will start to grow again. The trial is testing how well three new drugs work to prevent the tumour from growing again. The drugs are called celecoxib, docetaxel and zoledronic acid and are used with the hormone therapy.

As of 15/02/2011 the anticipated end date for this trial has been updated from 01/10/2012 to 01/12/2013.

As of 23/01/2013 the anticipated end date for this trial has been updated from 01/12/2013 to 01/12/2015. If new arms are add to the trial the end date will be extended further.
Lay summary http://www.cancerhelp.org.uk/trials/a-trial-looking-at-hormone-therapy-with-zoledronic-acid-docetaxel-or-celecoxib-for-prostate-cancer
Ethics approval West Midlands MREC on 04/10/2004 (ref: 04/MRE07/35)
Study design Randomised controlled trial
Countries of recruitment United Kingdom
Disease/condition/study domain Prostate Adenocarcinoma
Participants - inclusion criteria Current inclusion criteria as of 23/01/2013:
Patients must fulfil both of the criteria in Section 1 or one criterion in Section 2 or at least one criteria in Section 3. Additionally, all patients must fulfil the criteria in Section 4.

1 HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE - Both:
1.1. At least two of: Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10
1.2. Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU)

OR
2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE - At least one of:
2.1. Stage Tany N+ M0
2.2. Stage Tany Nany M+

OR
3. PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING - At least one of:
3.1. PSA ≥4ng/ml and rising with doubling time less than 6 months
3.2. PSA ≥20ng/ml
3.3. N+
3.4. M+

AND
4. FOR ALL PATIENTS
4.1. Histologically confirmed prostate adenocarcinoma
4.2. Intention to treat with long-term androgen deprivation therapy
4.3. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23
4.4 Have completed the appropriate investigations prior to randomisation
4.5. Adequate haematological function: neutrophil count >1.5x109/l and platelets >100x109/l
4.6. Estimated creatinine clearance >30ml/min
4.7. Serum potassium ≥3.5mmol/L
4.8. Written informed consent
4.9. Willing and expected to comply with follow-up schedule
4.10. Using effective contraceptive method if applicable

Previous inclusion criteria until 23/01/2013
Patients must fulfil one of the inclusion criteria in section one or one of the inclusion criteria in section two. Additionally, all patients must fulfil the inclusion criteria in section three:

Section one - high risk newly diagnosed patients must fulfil one of the following criteria:
1. Stage T3/4 N0 M0 histologically confirmed prostate adenocarcinoma with Prostate Specific Antigen (PSA) = 40 ng/ml or Gleason sum score eight to ten
2. Stage Tany N + M0 or Tany Nany M + histologically confirmed prostate adenocarcinoma
3. Multiple sclerotic bone metastases with a PSA = 100 ng/ml

Section two - patients with histologically confirmed prostate adenocarcinoma previously treated with radical surgery or radiotherapy that are now relapsing. (Please note that prior hormone therapy for localised disease must have been completed 12 months previously, have been no longer than 12 months in duration and given as adjuvant or neoadjuvant therap:
1. PSA = 4 ng/ml and rising with doubling time less than six months
2. PSA = 20 ng/ml

Section three - for all patients:
1. Intention to treat with long-term androgen suppression
2. Fit for all protocol treatment and follow-up, World Health Organisation (WHO) performance status zero to two
3. Have completed the appropriate investigations prior to randomisation
4. Adequate haematological function: neutrophil count more than 1.5 x 10^9 l and platelets more than 100 x 10^9 l
5. Adequate renal function: Serum creatinine less than 1.5 Upper Limit of Normal (ULN)
6. Adequate liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than 1.5 ULN, bilirubin less than ULN
7. Normal testosterone level prior to treatment
8. Written informed consent
9. Willing and expected to comply with follow-up schedule
Participants - exclusion criteria Current exclusion criteria as of 23/01/2013:
1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3.
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 physician, is likely to interfere with STAMPEDE treatment or assessment
5. Patients with active peptic ulceration, gastrointestinal bleeding, inflammatory bowel disease
6. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5
7. Any surgery (e.g. TURP) performed within the past 4 weeks
8. 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)6
• Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation
• Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg
9. Patients who have been scheduled to have major dental extractions within the next 2 years
10. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7
11. Prior exposure to abiraterone
12. Prior chemotherapy for prostate cancer
13. Prior therapy with zoledronic acid other than short-term treatment for hypercalcaemia
14. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2 of the protocol)

SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE
All patients meeting criteria above are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this “RT to the prostate” comparison are:
1. Newly diagnosed prostate cancer
2. Demonstrable M1 disease
3. No contraindication to radiotherapy e.g. no previous pelvic radiotherapy,
4. No previous radical prostatectomy
Patients meeting these criteria will have a chance to be allocated to Arms A and H.

Previous exclusion criteria until 23/01/2013:
1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in section two
2. Metastatic brain disease or leptomeningeal disease
3. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment
4. Symptomatic peripheral neuropathy grade two (National Cancer Institute Common Toxicity Criteria [NCI CTC])
5. Any surgery (e.g. transurethral resection of the prostate [TURP]) performed within the past four weeks
Anticipated start date 17/10/2005
Anticipated end date 01/12/2015
Status of trial Ongoing
Patient information material Patient information can be found at: http://www.stampedetrial.org
Target number of participants 3,300
Interventions Current interventions as of 23/01/2013:
Arm A = Androgen deprivation therapy (ADT) - control
Arm B = ADT + zoledronic acid
Arm C = ADT + docetaxel
Arm D = ADT + celecoxib
Arm E = ADT + zoledronic acid + docetaxel (NOW CLOSED)
Arm F = ADT + zoledronic acid + celecoxib (NOW CLOSED)
Arm G = ADT + abiraterone (included from protocol version 8.0):
Arm H = ADT + radiotherapy to the prostate (included from protocol version 9.0)

1. Zoledronic acid: Prostate cancer cells can spread to bones and weaken them. Zoledronic acid is a drug that reduces bone destruction and hardens bones. This may make them more resistant to attack by cancer cells.
2. Docetaxel: A drug that stops cells replicating that is currently being used to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel prolongs survival in men with relapsed metastatic prostate cancer.
3. Celecoxib: An aspirin-like drug that is used to treat arthritis. It slows down the growth of cancer cells in the laboratory. We wished to see if it had the same effect on cancer cells in patients. Recruitment to new patients for the evaluation of this drug is finished as a planned interim analysis failed to demonstrate sufficient activity.
4. Abiraterone (included from protocol version 8.0): An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume growth following castration based therapies. The agent prolongs survival when given to men following failure of docetaxel chemotherapy.
5. Prostate radiotherapy (included from protocol version 9.0): treatment with high-energy x-rays targeted to the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate gland as large trials have shown it improves survival times. We are not certain whether we should give radiotherapy to the prostate if the cancer has already spread.

Previous interventions until 23/01/2013:
Patients will be randomised to the control arm (Arm A) or one of the five investigational arms. All patients will receive androgen suppression (AS) to
castration level. The method of AS is a local choice but must be specified for each patient prior to randomisation. All trial treatments should commence as soon as practically possible after randomisation. Patients
having a bilateral orchidectomy should commence any additional treatment within four weeks of the operation unless there is a strong clinical reason not
to do so.

Arm A = Androgen suppression (AS) - control
Arm B = AS + zoledronic acid
Arm C = AS + docetaxel
Arm D = AS + celecoxib
Arm E = AS + zoledronic acid + docetaxel
Arm F = AS + zoledronic acid + celecoxib
Primary outcome measure(s) Added as of 11/09/2008:
Pilot phase: Safety
Efficacy Stage I-III: Failure-free survival (FFS)
Efficacy Stage IV: Overall survival
Secondary outcome measure(s) Added as of 11/09/2008:
Pilot phase:
1. Feasibility

Efficacy Stage I-III:
2. Overall survival (OS)
3. Toxicity
4. Skeletal related events

Efficacy Stage IV:
1. Quality of life
2. Cost effectiveness
3. Failure-free survival†
4. Toxicity
5. Skeletal related events
Sources of funding Cancer Research UK (UK)
Trial website http://www.stampedetrial.org
Publications 1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22452894
2. 2012 evaluation of trial design in http://www.ncbi.nlm.nih.gov/pubmed/22978443
Contact name Prof  Nicholas  James
  Address CRUK Institute for Cancer Studies
University of Birmingham
Edgbaston
  City/town Birmingham
  Zip/Postcode B15 2TT
  Country United Kingdom
Sponsor Medical Research Council (UK)
  Address c/o MRC Clinical Trials Unit
Aviation House
125 Kings Way
  City/town London
  Zip/Postcode WC2B 6NH
  Country United Kingdom
Date applied 02/02/2004
Last edited 23/01/2013
Date ISRCTN assigned 03/08/2004
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