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

Nicholas D James³  George Thalmann¹  Karen Sanders⁹  J Martin Russell⁵  Alastair WS Ritchie⁹  Gordana Jovic⁹  Charlene Green⁹  John Dwyer⁸  David P Dearnaley⁴  Johann de Bono⁴  John Anderson⁶  Claire Amos⁹  Noel W Clarke⁷  Malcolm D Mason²  Mahesh KB Parmar⁹  Matthew R Sydes⁹ 

[1] Inselspital, Bern, Switzerland;School of Medicine, Cardiff University, Cardiff, UK;School of Cancer Sciences, University of Birmingham, Birmingham, UK;Institute of Cancer Research and Royal Marsden Hospitals Foundation Trust, Sutton, UK;Beatson West of Scotland Cancer Centre, Glasgow, UK;The Royal Hallamshire Hospital, Sheffield, UK;The Christie and Salford Royal Hospitals Foundations Trusts, Manchester, UK;Prostate Cancer Support Federation, Stockport, UK;MRC Clinical Trials Unit, London, UK

关键词: Randomized controlled trial;    Methodology;    Prostate cancer;    Implementation;    Multi-arm multi-stage design;    Novel design;   

Others  :  1095336
DOI  :  10.1186/1745-6215-13-168

 received in 2012-03-09, accepted in 2012-08-16,  发布年份 2012

【 摘 要 】

Background

Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.

Methods

STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.

Results

(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.

(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.

Conclusions

The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.

Trial registration

ISRCTN78818544, NCT00268476

First patient into trial: 17 October 2005

First patient into abiraterone comparison: 15 November 2011

【 授权许可】

   
2012 Sydes et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Royston P, Parmar MKB, Qian W: Novel designs for multi-arm clinical trials with survival outcomes with an application in ovarian cancer. Stat Med 2003, 22:2239-2256.
• [2]Royston P, Barthel FMS, Parmar MKB, Choodari-Oskooei B, Isham V: Designs for clinical trials with time-to-event outcomes based on stopping guidelines for lack of benefit. Trials 2011, 12:81. BioMed Central Full Text
• [3]Parmar MKB, Barthel F, Sydes M, Langley R, Kaplan R, Eisenhauer E, Brady M, James N, Bookman MA, Swart AM, Qian W, Royston P: Speeding up the evaluation of New agents in cancer. J Natl Canc Inst 2008, 100:1204-1214.
• [4]James N, Sydes M, Clarke N, Mason M, Dearnaley D, Anderson J, Popert R, Sanders K, Morgan R, Stansfeld J, Dwyer J, Masters J, Parmar MKB: STAMPEDE: systemic therapy for advancing or metastatic prostate cancer - a multi-Arm multi-stage randomised controlled trial. Clin Onc 2008, 20:577-581.
• [5]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 MKB: Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU Int 2009, 103:464-469.
• [6]http://www.stampedetrial.org
• [7]Sydes MR, Parmar MKB, 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, 10:39. BioMed Central Full Text
• [8]Barthel FM-S, Royston P, Babiker A: A menu-driven facility for complex sample size calculation in randomized controlled trials with a survival or a binary outcome: Update. Stata J 2005, 5:123-129.
• [9]Barthel FM-S, Royston P, Parmar MKB: A menu-driven facility for sample-size calculation in novel multiarm, multistage randomized controlled trials with a time-to-event outcome. Stata J 2009, 9:505.
• [10]Royston P, Barthel FM: Projection of power and events in clinical trials with a time-to-event outcome. Stata J 2010, 10:1-9.
• [11]Kola I, Landis JR: Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004, 3:711-715.
• [12]Kumar A, Soares H, Wells R, Clarke M, Hozo I, Bleyer A, Reaman G, Chalmers I, Djulbegovic B: Are experimental treatments for cancer in children superior to established treatments? Observational study of randomised controlled trials by the Children's Oncology Group. BMJ 2005, 331:1295.
• [13]Roberts TG Jr, Lynch TJ Jr, Chabner BA: The phase III trial in the era of targeted therapy: unraveling the "go or no go" decision. J Clin Oncol 2003, 21:3683-3695.
• [14]James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AWS, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MKB: 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, 13:549-558.
• [15]James ND, Sydes MR, Mason MD, Clarke NW, Dearnaley DP, Dwyer J, Jovic G, Russell JM, Thalmann G, Parmar MKB: Celecoxib plus hormone therapy Vs hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE randomised controlled trial (MRC PR08). Eur J Cancer 2011, (Suppl 2):11.
• [16]de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010, 376:1147-1154.
• [17]Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010, 363:411-422.
• [18]Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernas B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS: Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007, 8:587-594.
• [19]Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 2010, 375:1437-1446.
• [20]Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009, 324:787-790.
• [21]Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller MDK, et al.: Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New Engl J Med 2012. Published online 15-Aug-2012
• [22]Hussain M, Smith MR, Sweeney C, Corn PG, Elfiky A, Gordon MS, Haas NB, Harzstark AL, Kurzrock R, Lara P, Lin C, Sella A, Small EJ, Spira AI, Vaishampayan UN, Vogelzang NJ, Scheffold C, Ballinger MD, Schimmoller F, Smith DC: Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial. J Clin Oncol 2011, 29:4516.
• [23]Attard G, Richards J, de Bono JS: New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Clin Cancer Res 2011, 17:1649-1657.
• [24]Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C, Molina A, Anand A, Koscuiszka M, Larson SM, Schwartz LH, Fleisher M, Scher HI: Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010, 28:1496-1501.
• [25]Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR, Hunt J, Messiou C, Parker C, Dearnaley D, Swennenhuis JF, Terstappen LW, Lee G, Kheoh T, Molina A, Ryan CJ, Small E, Scher HI, de Bono JS: Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010, 28:1489-1495.
• [26]Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, Martins V, Lee G, Kheoh T, Kim J, Molina A, Small EJ: Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 2010, 28:1481-1488.
• [27]de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Hagg CM, Scher HI, COU-AA-301 Investigators, COU-AA-301 Investigators: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011, 364:1995-2005.
• [28]de Bono JS, Ashworth A: Translating cancer research into targeted therapeutics. Nature 2010, 467:543-549.
• [29]Group obotC-A-S, Scher HI, Logothetis C, Molina A, Goodman OB, Sternberg CN, Chi KN, Kheoh TS, Haqq CM, Fizazi K, Bono JSD: Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy. J Clin Oncol 2011, 29:4.
• [30]Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fossa SD: Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009, 373:301-308.
• [31]Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MKB, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W, for the NCIC CTG PR.3/MRC UK PR07 investigators, for the NCIC CTG PR.3/MRC UK PR07 investigators: Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011, 378:2104-2111.
• [32]Pocock S: Clinical Trials: A Practical Approach. New York: Wiley; 1983.
• [33]Taves DR: Minimization: a new method of assigning patients to treatment and control groups. Clin Pharmacol Ther 1974, 15:443-453.