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

• 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 ]

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.

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 5,000 patients will join the trial with answers becoming available over 7 to 12 years.

OBJECTIVES:

Primary

• Compare the safety of Androgen Deprivation Therapy (ADT) alone vs ADT in varying combinations with zoledronic acid, docetaxel, abiraterone and/or radiotherapy to the prostate (and previously celecoxib) 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 randomized to 1 of 6 treatment arms.

• 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.
• 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.
• 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.
• 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.

• 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.

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. Core funding: Medical Research Council PROJECTED ACCRUAL: Approximately 5000 patients will be accrued for this study

• Drug: celecoxib
• Drug: docetaxel
• Drug: prednisolone
• Drug: releasing hormone agonist therapy
• Drug: zoledronic acid
• Drug: abiraterone
• Procedure: orchiectomy
• Radiation: Radiotherapy to the prostate

• Active Comparator: Arm A Androgen Deprivation Therapy [ADT]
  (plus Radiotherapy for newly-diagnosed non-metastatic disease)[Control]
  Interventions:

  • Drug: releasing hormone agonist therapy
  • Procedure: orchiectomy
• Experimental: Arm B (ADT + zoledronic acid)
  Interventions:

  • Drug: releasing hormone agonist therapy
  • Drug: zoledronic acid
  • Procedure: orchiectomy
• Experimental: Arm C (ADT + docetaxel + prednisolone)
  Interventions:

  • Drug: docetaxel
  • Drug: prednisolone
  • Drug: releasing hormone agonist therapy
  • Procedure: orchiectomy
• Experimental: Arm D (ADT + celecoxib) NO LONGER RECRUITING
  Interventions:

  • Drug: docetaxel
  • Drug: prednisolone
  • Drug: releasing hormone agonist therapy
  • Drug: zoledronic acid
  • Procedure: orchiectomy
• Experimental: Arm E (ADT + zoledronic acid + docetaxel + prednisolone)
  Interventions:

  • Drug: releasing hormone agonist therapy
  • Drug: abiraterone
  • Procedure: orchiectomy
• Experimental: Arm F (ADT + zoledronic acid + celecoxib) NO LONGER RECRUITING
  Interventions:

  • Drug: celecoxib
  • Drug: releasing hormone agonist therapy
  • Procedure: orchiectomy
• Experimental: Arm G (ADT + abiraterone)
  Interventions:

  • Drug: celecoxib
  • Drug: releasing hormone agonist therapy
  • Procedure: orchiectomy
• Experimental: Arm H (ADT + radiotherapy to the prostate)
  Interventions:

  • Drug: releasing hormone agonist therapy
  • Procedure: orchiectomy
  • Radiation: Radiotherapy to the prostate

• James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Anderson J, Popert RJ, Sanders K, Morgan RC, Stansfeld J, Dwyer J, Masters J, Parmar MK. Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU Int. 2009 Feb;103(4):464-9. Epub 2008 Oct 8.
• James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MK; STAMPEDE investigators. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012 May;13(5):549-58. Epub 2012 Mar 26.
• Sydes MR, Parmar MK, James ND, Clarke NW, Dearnaley DP, Mason MD, Morgan RC, Sanders K, Royston P. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009 Jun 11;10:39.
• Sydes MR, Parmar MK, Mason MD, Clarke NW, Amos C, Anderson J, de Bono J, Dearnaley DP, Dwyer J, Green C, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann G, James ND. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012 Sep 15;13:168. doi: 10.1186/1745-6215-13-168.
• Huang X, Chau CH, Figg WD. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures. J Hematol Oncol. 2012 Jul 2;5:35. doi: 10.1186/1756-8722-5-35.

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 of the protocol.

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 active peptic ulceration, gastrointestinal bleeding, inflammatory bowel disease VI. Symptomatic peripheral neuropathy grade <2 (NCI CTC)5 VII. Any surgery (e.g. TURP) performed within the past 4 weeks

VIII. 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 IX. Patients who have been scheduled to have major dental extractions within the next 2 years X. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 XI. Prior exposure to abiraterone XII. Prior chemotherapy for prostate cancer XIII. Prior therapy with zoledronic acid other than short-term treatment for hypercalcaemia XIV. 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:

• Newly diagnosed prostate cancer
• Demonstrable M1 disease
• No contraindication to radiotherapy e.g. no previous pelvic radiotherapy,
• No previous radical prostatectomy

Patients meeting these criteria will have a chance to be allocated to Arms A and H.