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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Medical Research Council
Sponsor:
Information provided by (Responsible Party):
Medical Research Council
ClinicalTrials.gov Identifier:
NCT00268476
First received: December 20, 2005
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

Prostate cancers depend upon the male hormone testosterone for their growth. Lowering testosterone levels (either by removing all or part of both testes, or by giving anti-hormone treatment) slows the growth of prostate cancers. This type of treatment is called hormone treatment and is often used when prostate cancers have spread outside of the prostate gland. Although hormone treatment is usually successful at stopping the cancer growing for a period of time, the cancer will begin to grow again in most men.

There are increasing numbers of treatments available for advanced prostate cancer. These treatments are usually used in prostate cancer when hormone treatment is no longer effective and the cancer has started to grow again. The aim of this trial, which is called STAMPEDE, is to assess five of these treatments, given earlier in the course of the disease in combination with hormone treatment.

The treatments assessed during the trial are:

  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, Docetaxel is currently being used to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel is already known to prolong survival in men with relapsed metastatic prostate cancer.
  3. Celecoxib: An aspirin-like drug that is used to treat arthritis. Celecoxib 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 pre-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. This agent is given along with prednisolone and is already known to prolong 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 interested in whether we should give radiotherapy to the prostate if the cancer has already spread.
  6. Enzalutamide (included from protocol version 12.0): This is a blocker of androgen receptors. These stimulate the cancer when hormone therapies have failed. Enzalutamide may be mutually complementary to abiraterone in terms of blocking mechanisms of resistance. The agent prolongs survival when given to men following failure of docetaxel chemotherapy.

STAMPEDE will look at the effect of combining one or two of the treatments described above with hormone treatment. A computer program will be used to allocate which treatment the patient receives, using a chance process. The trial will look at the effects of the combined treatments on quality of life and find out whether the new treatment combinations increase the time when the cancer is not growing and ultimately results in patients living longer. The study will also look at which treatment provides the greater value for money for the health service. More than 8,000 patients will join the trial with answers becoming available over 7 to 12 years.


Condition Intervention Phase
Prostate Cancer
Drug: celecoxib
Drug: docetaxel
Drug: prednisolone
Drug: ADT
Drug: zoledronic acid
Drug: abiraterone
Procedure: orchiectomy
Radiation: Radiotherapy to the prostate
Drug: enzalutamide
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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 in Treating Patients With Locally Advanced or Metastatic Prostate Cancer

Resource links provided by NLM:


Further study details as provided by Medical Research Council:

Primary Outcome Measures:
  • Overall survival [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Failure-free survival [ Designated as safety issue: No ]
  • Cost effectiveness by EuroQol [ Designated as safety issue: No ]
  • Quality of life (QOL) by EORTC QOL Questionnaire C30 and prostate specific 25-item [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
  • Skeletal related events [ Designated as safety issue: No ]

Estimated Enrollment: 8100
Study Start Date: September 2005
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A Androgen Deprivation Therapy [ADT]
(plus Radiotherapy for newly-diagnosed non-metastatic disease)[Control]
Drug: ADT Procedure: orchiectomy
Experimental: Arm B (ADT + zoledronic acid)
NO LONGER RECRUITING
Drug: ADT Drug: zoledronic acid Procedure: orchiectomy
Experimental: Arm C (ADT + docetaxel + prednisolone)
NO LONGER RECRUITING
Drug: docetaxel Drug: prednisolone Drug: ADT Procedure: orchiectomy
Experimental: Arm D (ADT + celecoxib)
NO LONGER RECRUITING
Drug: docetaxel Drug: prednisolone Drug: ADT Drug: zoledronic acid Procedure: orchiectomy
Experimental: Arm E (ADT + zoledronic acid + docetaxel + prednisolone)
NO LONGER RECRUITING
Drug: ADT Drug: abiraterone Procedure: orchiectomy
Experimental: Arm F (ADT + zoledronic acid + celecoxib)
NO LONGER RECRUITING
Drug: celecoxib Drug: ADT Procedure: orchiectomy
Experimental: Arm G (ADT + abiraterone)
NO LONGER RECRUITING
Drug: celecoxib Drug: ADT Procedure: orchiectomy
Experimental: Arm H (ADT + radiotherapy to the prostate) Drug: ADT Procedure: orchiectomy Radiation: Radiotherapy to the prostate
Experimental: Arm J (ADT + abiraterone + enzalutamide) Drug: prednisolone Drug: ADT Drug: abiraterone Drug: enzalutamide

Detailed Description:

OBJECTIVES:

Primary

  • Compare the safety of Androgen Deprivation Therapy (ADT) alone vs ADT in varying combinations with enzalutamide and abiraterone and/or radiotherapy to the prostate (and previously celecoxib, zoledronic acid, docetaxel and abiraterone alone) in patients with locally advanced or metastatic prostate cancer.
  • Compare failure-free survival and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter, pilot study. Patients are currently randomised to 1 of 3 treatment arms (A, H and J). The other arms are now closed to recruitment.

  • Arm A (Androgen Deprivation Therapy [ADT] (plus RT for newly-diagnosed non-metastatic disease) [control]): Patients undergo bilateral orchidectomy or receive luteinizing hormone-releasing hormone (LHRH) analogues to achieve castration levels of testosterone.
  • Arm B (ADT and zoledronic acid): Patients undergo ADT (+/- RT) as in arm A. Patients also receive zoledronic acid IV over 15 minutes on day 1. Treatment repeats every 3 weeks for 6 courses and then every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity (no longer recruiting).
  • Arm C (ADT, docetaxel, and prednisolone): Patients undergo ADT (+/- RT) as in arm A. Patients also receive docetaxel IV over 1 hour on day 1 and oral prednisolone twice daily on days 1-21. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity (no longer recruiting).
  • Arm D (ADT and celecoxib): Patients undergo ADT as in arm A. Patients also receive oral celecoxib twice daily for 1 year in the absence of disease progression or unacceptable toxicity (no longer recruiting).
  • Arm E (ADT, zoledronic acid, docetaxel, and prednisolone): Patients undergo ADT (+/- RT) as in arm A. Patients also receive zoledronic acid as in arm B and docetaxel and prednisolone as in arm C (no longer recruiting)..
  • Arm F (ADT, zoledronic acid, and celecoxib): Patients undergo ADT as in arm A. Patients also receive zoledronic acid as in arm B and celecoxib as in arm D (no longer recruiting).
  • Arm G (ADT and abiraterone): Patients undergo ADT (+/- RT) as in arm A. Patients also receive oral abiraterone once daily together with prednisolone or prednisone 5mg daily to prevent secondary ACTH excess (no longer recruiting).
  • Arm H (ADT and radiotherapy to the prostate): Patients (newly-diagnosed-metastatic only) undergo ADT, as in arm A. Patients also receive radiotherapy to the prostate. Two radiotherapy dose-fractionation schedules are permitted. In either case, radiotherapy is prescribed such that at least 95% of the PTV receives the prescribed dose:

    36Gy in 6 fractions of 6Gy, administered weekly over 6 consecutive weeks or 55Gy in 20 fractions of 2.75Gy, administered daily, five days per week, over 4 consecutive weeks.

  • Arm J (ADT, enzalutamide and abiraterone): Patients undergo ADT, as in arm A. Patients also receive oral enzalutamide once daily and abiraterone once daily together with prednisolone or prednisone 5mg daily to prevent secondary ACTH excess.

After completion of study treatment, patients are followed periodically thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK. Grant funding: Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas. Core funding: Medical Research Council PROJECTED ACCRUAL: Approximately 5000 patients will be accrued for this study

  Eligibility

Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE

Both:

At least two of:

  • Stage 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 sought in advance of consent, after discussion with MRC CTU)

OR NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE

At least one of:

  • Stage Tany N+ M0
  • Stage Tany Nany M+

OR PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING1

At least one of:

  • PSA ≥4ng/ml and rising with doubling time less than 6 months
  • PSA ≥20ng/ml
  • N+
  • M+

AND FOR ALL PATIENTS I. Histologically confirmed prostate adenocarcinoma

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

III. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23

IV. Have completed the appropriate investigations prior to randomisation

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

VI. Estimated creatinine clearance >30ml/min

VII. Serum potassium ≥3.5mmol/L

VIII. Written informed consent

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

X. Using effective contraceptive method if applicable

PATIENT EXCLUSION CRITERIA Patients must not fulfil any of the criteria, below. I. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3

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 physician, is likely to interfere with STAMPEDE treatment or assessment

V. Patients with contra-indications to prednisolone, including active peptic ulceration or a history of gastrointestinal bleeding

VI. Patients with active inflammatory bowel disease

VII. Symptomatic peripheral neuropathy grade (NCI CTC)

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

IX. 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)
  • 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

X. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)

XI. Prior exposure to abiraterone

XII. Prior exposure to enzalutamide

XIII. Prior chemotherapy for prostate cancer

XIV. Prior therapy with zoledronic acid or other bisphosphonates other than treatment for hypercalcaemia or low bone density

XV. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2)

XVI. History of seizure including any febrile seizure, loss of consciousness, or transient ischaemic attack within 12 months of randomisation or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization)

XVII. Unexplained history of loss of consciousness within 12 months of randomisation

XVIII. Operation of heavy machinery during treatment

SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE

All patients meeting criteria in Section 4.1 and 4.2 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:

  • Newly-diagnosed prostate cancer
  • Demonstrable M1 disease
  • No contraindication to radiotherapy e.g. no previous pelvic radiotherapy and no history of inflammatory bowel disease
  • No previous radical prostatectomy

Any patients meeting these criteria will have a chance to be allocated to Arm H.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00268476

Contacts
Contact: Francesca Schiavone +44 (0)20 7670 4632 mrcctu.stampede@ucl.ac.uk

  Show 120 Study Locations
Sponsors and Collaborators
Medical Research Council
Investigators
Study Chair: Nicholas D. James, MD University Hospital Birmingham
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Medical Research Council
ClinicalTrials.gov Identifier: NCT00268476     History of Changes
Other Study ID Numbers: CDR0000455008, MRC-STAMPEDE, EU-205102, MRC-PR08, ISRCTN78818544, EUDRACT-2004-000193-31
Study First Received: December 20, 2005
Last Updated: July 24, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Medical Research Council:
stage III prostate cancer
stage IV prostate cancer
recurrent prostate cancer
adenocarcinoma of the prostate

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Docetaxel
Prednisolone
Methylprednisolone Hemisuccinate
Celecoxib
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Zoledronic acid
Diphosphonates
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic

ClinicalTrials.gov processed this record on September 30, 2014