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Phase I–II Targeted Treatments

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Management of Castration Resistant Prostate Cancer

Part of the book series: Current Clinical Urology ((CCU))

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Abstract

Multiple survival-prolonging treatments have now been established in castration-resistant prostate cancer (CRPC) and molecular analyses have identified further potential therapeutic targets. Optimizing the clinical development of novel anticancer drugs therefore remains an urgent priority in CRPC. In this chapter we will review issues specific to conducting Phase I and II clinical trials of targeted therapies for men with CRPC, including: trial design; selection of trial participants; safety and efficacy monitoring in trial participants; and the acquisition of tumor tissue for predictive and pharmacodynamic studies.

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References

  1. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89(15):1138–47.

    Article  CAS  PubMed  Google Scholar 

  2. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101(10):708–20.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med. 1998;17(10):1103–20.

    Article  CAS  PubMed  Google Scholar 

  4. Eisenberger MA, Sinibaldi VJ, Reyno LM, Sridhara R, Jodrell DI, Zuhowski EG, et al. Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer. J Clin Oncol. 1995;13(9):2174–86.

    CAS  PubMed  Google Scholar 

  5. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 2010;375(9724):1437–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97.

    Article  CAS  PubMed  Google Scholar 

  7. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364(21):1995–2005.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A’Hern R, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8.

    Article  CAS  PubMed  Google Scholar 

  10. Patel JC, Maughan BL, Agarwal AM, Batten JA, Zhang TY, Agarwal N. Emerging molecularly targeted therapies in castration refractory prostate cancer. Prostate Cancer. 2013;2013:981684.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Arbuck SG. Workshop on phase I study design. Ninth NCI/EORTC new drug development symposium, Amsterdam, March 12, 1996. Ann Oncol. 1996;7(6): 567–73.

    Article  CAS  PubMed  Google Scholar 

  12. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24(7): 1813–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592–605.

    Article  CAS  PubMed  Google Scholar 

  14. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28): 4563–71.

    Article  CAS  PubMed  Google Scholar 

  15. Engels FK, Loos WJ, van der Bol JM, de Bruijn P, Mathijssen RH, Verweij J, et al. Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomized pharmacokinetic study. Clin Cancer Res. 2011;17(2):353–62.

    Article  CAS  PubMed  Google Scholar 

  16. Marcucci F, Corti A. Improving drug penetration to curb tumor drug resistance. Drug Discov Today. 2012;17(19–20):1139–46.

    Article  CAS  PubMed  Google Scholar 

  17. Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010;16(6):1726–36.

    Article  PubMed  Google Scholar 

  18. Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, et al. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a children’s oncology group study. J Clin Oncol. 2011;29(33):4351–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Yap TA, Pezaro CJ, de Bono JS. Cabazitaxel in metastatic castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2012;12(9):1129–36.

    Article  CAS  PubMed  Google Scholar 

  20. Omlin A, Pezaro C, Mukherji D, Mulick Cassidy A, Sandhu S, Bianchini D, et al. Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. Eur Urol. 2013;64(2): 300–6.

    Article  PubMed  Google Scholar 

  21. Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Eisenhauer EA, Seymour LK. Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer. 2008;44(1):25–9.

    Article  CAS  PubMed  Google Scholar 

  22. Goodwin R, Giaccone G, Calvert H, Lobbezoo M, Eisenhauer EA. Targeted agents: how to select the winners in preclinical and early clinical studies? Eur J Cancer. 2012;48(2):170–8.

    Article  PubMed  Google Scholar 

  23. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–9.

    Article  PubMed  Google Scholar 

  24. Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496–501.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28(9):1489–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Gray R, Manola J, Saxman S, Wright J, Dutcher J, Atkins M, et al. Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group. Clin Cancer Res. 2006;12(7 Pt 1):1966–9.

    Article  CAS  PubMed  Google Scholar 

  27. Brown SR, Gregory WM, Twelves CJ, Buyse M, Collinson F, Parmar M, et al. Designing phase II trials in cancer: a systematic review and guidance. Br J Cancer. 2011;105(2):194–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Anderson J, et al. Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU Int. 2009;103(4):464–9.

    Article  CAS  PubMed  Google Scholar 

  29. A’Hern R, de Bono JS, Sandhu S, Kalaitzaki E, Usdin M, Hall EE. Phase II investigation of a PARP inhibitor (olaparib) in castration resistant prostate cancer (CRPC) which incorporates the possibility that treatment effect may be restricted to biomarker defined subgroups. Trials. 2011;12(supp 1):A88.

    Article  PubMed Central  Google Scholar 

  30. Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan 2006. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003617.pdf.

  31. Guidance for industry: adaptive design clinical trials for drugs and biologics 2010. Available from: http://www.fda.gov/downloads/Drugs/guidancecomplianceregulatoryinformation/guidances/ucm201790.pdf.

  32. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein Jr GR, Tsao A, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1): 44–53.

    Article  CAS  PubMed  Google Scholar 

  33. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86(1): 97–100.

    Article  CAS  PubMed  Google Scholar 

  34. Wang SJ, James Hung HM, O’Neill RT. Impacts on type I error rate with inappropriate use of learn and confirm in confirmatory adaptive design trials. Biomed J. 2010;52(6):798–810.

    Google Scholar 

  35. Chan JK, Ueda SM, Sugiyama VE, Stave CD, Shin JY, Monk BJ, et al. Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success? J Clin Oncol. 2008; 26(9):1511–8.

    Article  PubMed  Google Scholar 

  36. Antonarakis ES, Eisenberger MA. Phase III trials with docetaxel-based combinations for metastatic castration-resistant prostate cancer: time to learn from past experiences. J Clin Oncol. 2013;31(14): 1709–12.

    Article  CAS  PubMed  Google Scholar 

  37. Freidlin B, McShane LM, Polley MY, Korn EL. Randomized phase II trial designs with biomarkers. J Clin Oncol. 2012;30(26):3304–9.

    Article  PubMed Central  PubMed  Google Scholar 

  38. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.

    Article  PubMed  Google Scholar 

  39. Mateo J, Ong M, Tan DS, Gonzalez MA, de Bono JS. Appraising iniparib, the PARP inhibitor that never was-what must we learn? Nat Rev Clin Oncol. 2013;10(12):688–96.

    Google Scholar 

  40. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16(1):31–41.

    Article  CAS  PubMed  Google Scholar 

  41. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148–59.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Pezaro C, Omlin A, Lorente D, Nava Rodrigues D, Ferraldeschi R, Bianchini D, et al. Visceral disease in castration-resistant prostate cancer. Eur Urol. 2014;65(2):270–3.

    Google Scholar 

  43. Bachelot T, Ray-Coquard I, Catimel G, Ardiet C, Guastalla JP, Dumortier A, et al. Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials. Ann Oncol. 2000;11(2):151–6.

    Article  CAS  PubMed  Google Scholar 

  44. Arkenau HT, Barriuso J, Olmos D, Ang JE, de Bono J, Judson I, et al. Prospective validation of a prognostic score to improve patient selection for oncology phase I trials. J Clin Oncol. 2009;27(16):2692–6.

    Article  CAS  PubMed  Google Scholar 

  45. Wheler J, Tsimberidou AM, Hong D, Naing A, Falchook G, Piha-Paul S, et al. Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience. Clin Cancer Res. 2012;18(10):2922–9.

    Article  CAS  PubMed  Google Scholar 

  46. Olmos D, Baird RD, Yap TA, Massard C, Pope L, Sandhu SK, et al. Baseline circulating tumor cell counts significantly enhance a prognostic score for patients participating in phase I oncology trials. Clin Cancer Res. 2011;17(15):5188–96.

    Article  CAS  PubMed  Google Scholar 

  47. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644–8.

    Article  CAS  PubMed  Google Scholar 

  48. Reid AH, Attard G, Brewer D, Miranda S, Riisnaes R, Clark J, et al. Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer. Mod Pathol. 2012;25(6):902–10.

    Article  CAS  PubMed  Google Scholar 

  49. Mosquera JM, Beltran H, Park K, MacDonald TY, Robinson BD, Tagawa ST, et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia. 2013;15(1):1–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Armstrong AJ, Eisenberger MA, Halabi S, Oudard S, Nanus DM, Petrylak DP, et al. Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur Urol. 2012; 61(3):549–59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer. 2010;10(7):514–23.

    Article  CAS  PubMed  Google Scholar 

  52. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009; 115(16):3670–9.

    Article  CAS  PubMed  Google Scholar 

  53. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  PubMed  Google Scholar 

  54. Galasko CS. The significance of occult skeletal metastases, detected by skeletal scintigraphy, in patients with otherwise apparently ‘early’ mammary carcinoma. Br J Surg. 1975;62(9):694–6.

    Article  CAS  PubMed  Google Scholar 

  55. Galasko CS. Problems associated with the detection of skeletal metastases. J R Soc Med. 1978;71(1): 38–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Brown MS, Chu GH, Kim HJ, Allen-Auerbach M, Poon C, Bridges J, et al. Computer-aided quantitative bone scan assessment of prostate cancer treatment response. Nucl Med Commun. 2012;33(4): 384–94.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  CAS  PubMed  Google Scholar 

  58. Lecouvet FE, El Mouedden J, Collette L, Coche E, Danse E, Jamar F, et al. Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99 m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Eur Urol. 2012;62(1):68–75.

    Article  PubMed  Google Scholar 

  59. Evangelista L, Zattoni F, Guttilla A, Saladini G, Colletti PM, Rubello D. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nucl Med. 2013;38(5):305–14.

    Article  PubMed  Google Scholar 

  60. Scher HI, Heller G, Molina A, Kheoh TS, Attard G, Moreira J, et al. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus prednisone (P) post docetaxel. J Clin Oncol. 2011;29(suppl; abstr LBA4517).

    Google Scholar 

  61. Scher HI, Heller G, Molina A, Attard G, McCormack R, Riisnaes R, et al. Evaluation of a composite biomarker panel including circulating tumor cell (CTC) enumeration as a surrogate for survival in metastatic castration-resistant prostate cancer (mCRPC). In: The European cancer congress; 27 September – 1 October; Amsterdam 2013. Abstr. 2851.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Prostate Cancer Targeted Therapy Group, Sutton, UK

    Carmel Pezaro MBChB, DMedSc, FRACP

  2. Royal Marsden NHS Foundation Trust, Section of Medicine, Sycamore House, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Aurelius Omlin MD

  3. Royal Marsden HNS Foundation Trust, Drug Development Unit, Sycamore House, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Johann S. de Bono MBChB, FRCP, MSc, PhD

Authors
  1. Carmel Pezaro MBChB, DMedSc, FRACP
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  2. Aurelius Omlin MD
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  3. Johann S. de Bono MBChB, FRCP, MSc, PhD
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Corresponding author

Correspondence to Johann S. de Bono MBChB, FRCP, MSc, PhD .

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Editors and Affiliations

  1. Department of Surgery, University of Montreal Hospital Center, Montreal, Québec, Canada

    Fred Saad

  2. Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, USA

    Mario A. Eisenberger

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Pezaro, C., Omlin, A., de Bono, J.S. (2014). Phase I–II Targeted Treatments. In: Saad, F., Eisenberger, M. (eds) Management of Castration Resistant Prostate Cancer. Current Clinical Urology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1176-9_13

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  • DOI: https://doi.org/10.1007/978-1-4939-1176-9_13

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