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Innovations in Clinical Trial Design in the Era of Molecular Profiling

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Molecular Profiling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1606))

Abstract

Historically, cancer has been studied, and therapeutic agents have been evaluated based on organ site, clinical staging, and histology. The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available, and this has necessitated an evolution in clinical trial design. The traditional, large phase II and phase III adjuvant trial models need to be replaced with smaller, shorter, and more focused trials. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames. New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need.

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References

  1. DeMichele A, Yee D, Berry DA et al (2015) The neoadjuvant model is still the future for drug development in breast cancer. Clin Cancer Res 21:2911–2915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. LoRusso PM, Anderson AB, Boerner SA et al (2010) Making the investigational oncology pipeline more efficient and effective: are we headed in the right direction? Clin Cancer Res 16:5956–5962

    Article  PubMed  Google Scholar 

  3. Renfro LA, An M-W, Mandrekar SJ (2016) Precision oncology: a new era of cancer clinical trials. Cancer Lett 387:121–126

    Article  PubMed  Google Scholar 

  4. Berry DA (2015) The brave new world of clinical cancer research: adaptive biomarker-driven trials integrating clinical practice with clinical research. Mol Oncol 9:951–959

    Article  PubMed  PubMed Central  Google Scholar 

  5. Berry DA (2016) Emerging innovations in clinical trial design. Clin Pharma Ther 99:82–91

    Article  CAS  Google Scholar 

  6. US Food and Drug Administration (2007) Guidance for industry. Clinical trial endpoints for the approval of cancer drugs and biologics. http://wwwfdagov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590pdf. Accessed 8 Aug 2016

  7. US Food and Drug Administration (2012) Guidance for Industry. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm305501.pdf. Accessed 8 Aug 2016

  8. Pazdur R (2008) Endpoints for assessing drug activity in clinical trials. Oncologist 13(Suppl 2):19–21

    Article  PubMed  Google Scholar 

  9. Glynne-Jones R, Mawdsley S, Pearce T et al (2006) Alternative clinical end points in rectal cancer--are we getting closer? Ann Oncol 17:1239–1248

    Article  CAS  PubMed  Google Scholar 

  10. Scott J, McGettigan G (2005) Regulatory approvals for oncology products based on accelerated clinical development and limited data packages-2. Regul Rapporteur 2:6–15

    Google Scholar 

  11. Schuetze SM, Baker LH, Benjamin RS et al (2008) Selection of response criteria for clinical trials of sarcoma treatment. Oncologist 13(Suppl 2):32–40

    Article  PubMed  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) 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 92:205–216

    Article  CAS  Google Scholar 

  13. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  14. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  CAS  PubMed  Google Scholar 

  15. Alves RC, Alves D, Guz B et al (2011) Advanced hepatocellular carcinoma. Review of targeted molecular drugs. Ann Hepatol 10:21–27

    PubMed  Google Scholar 

  16. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  17. Sataloff DM, Mason BA, Prestipino AJ et al (1995) Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg 180:297–306

    CAS  PubMed  Google Scholar 

  18. Honkoop AH, van Diest PJ, de Jong JS et al (1998) Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. Br J Cancer 77:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bonadonna G, Valagussa P, Brambilla C et al (1998) Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93–100

    Article  CAS  PubMed  Google Scholar 

  20. Fisher B, Bryant J, Wolmark N et al (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685

    Article  CAS  PubMed  Google Scholar 

  21. Ogston KN, Miller ID, Payne S et al (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12:320–327

    Article  PubMed  Google Scholar 

  22. Bear HD, Anderson S, Smith RE et al (2006) Sequential preoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 24:2019–2027

    Article  CAS  PubMed  Google Scholar 

  23. Kaufmann M, Hortobagyi GN, Goldhirsch A et al (2006) Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 24:1940–1949

    Article  PubMed  Google Scholar 

  24. Esserman LJ, Berry DA, DeMichele A et al (2012) Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL—CALGB 120007/150012, ACRIN 6657. J Clin Oncol 30:3242–3249

    Article  PubMed  PubMed Central  Google Scholar 

  25. von Minckwitz G, Untch M, Blohmer J-U et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30:1796–1804

    Article  Google Scholar 

  26. Korn EL, Sachs MC, McShane LM (2016) Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann Oncol 27:10–15

    Article  CAS  PubMed  Google Scholar 

  27. Cortazar P, Geyer CE (2015) Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 22:1441–1446

    Article  PubMed  Google Scholar 

  28. Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422

    Article  PubMed  Google Scholar 

  29. Peintinger F, Sinn B, Hatzis C et al (2015) Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy. Mod Pathol 28:913–920

    Article  PubMed  PubMed Central  Google Scholar 

  30. Esserman LJ, DeMichele A (2014) Accelerated approval for pertuzumab in the neoadjuvant setting: winds of change? Clin Cancer Res 20:3632–3636

    Article  CAS  PubMed  Google Scholar 

  31. Swain SM, Kim SB, Cortes J et al (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gianni L, Pienkowski T, Im YH et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory or early HER2-positive breasts cancer (NeoSphere): a randomized multicenter, open-label, phase 2 trial. Lancet Oncol 13:25–32

    Article  CAS  PubMed  Google Scholar 

  33. Schneeweiss A, Chia S, Hickish T et al (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278–2284

    Article  CAS  PubMed  Google Scholar 

  34. Spira A, Edmiston KH (2012) Clinical trial design in the age of molecular profiling. In: Espina V, Liotta LA (eds) Molecular profiling: methods and protocols, 1st edn. Springer, New York

    Google Scholar 

  35. Renfro LA, Mallick H, An M-W et al (2016) Clinical trial designs incorporating predictive biomarkers. Cancer Treat Rev 43:74–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Redig AJ, Jänne PA (2015) Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol 33:975–977

    Article  CAS  PubMed  Google Scholar 

  37. Lopez-Chavez A, Thomas A, Rajan A et al (2015) Molecular profiling and target therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 33:1000–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. TAPUR: ASCO’s first clinical trial addresses critical gaps in understanding of and access to targeted therapies. http://pallonc.org/tapur-asco’s-first-clinical-trial-addresses-critical-gaps-understanding-and-access-targeted. Accessed 6 Aug 2016

  39. NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial. http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. Accessed 6 Aug 2016

  40. Executive summary: Interim analysis of the NCI-MATCH trial. http://ecog-acrin.org/nci-match-eay131/interim-analysis. Accessed 8 Aug 2016

  41. Dolgin E (2016) Shoddy biopsies deny cancer patients a shot at personalized treatment. https://www.statnews.com/2016/01/22/precision-medicine-cancer-biopsies/. Accessed 8 Aug 2016

  42. Rugo HS, Olopade OI, DeMichele A et al (2016) Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 375:23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Park JW, Liu MC, Yee D et al (2016) Adaptive randomization of neratinib in early breast cancer. N Engl J Med 375:11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jameson GS, Petricoin EF, Sachdev J et al (2014) A pilot study utilizing multi-omic molecular profiling to find potential targets and select individualized treatments for patients with previously treated metastatic breast cancer. Breast Cancer Res Treat 147:579–588

    Article  CAS  PubMed  Google Scholar 

  45. Herzog TJ, Spetzler D, Xiao N et al (2016) Impact of molecular profiling on overall survival of patients with advanced ovarian cancer. Oncotarget 7:19840–19849

    PubMed  PubMed Central  Google Scholar 

  46. Conrads TP, Petricoin EF III (2016) The Obama administration’s cancer moonshot: a call for proteomics. Clin Cancer Res 22:4556–4558

    Google Scholar 

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Author information

Authors and Affiliations

  1. Center for Applied Proteomics and Molecular Medicine, Institute for Advanced Biomedical Research, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA

    Julia D. Wulfkuhle Ph.D. & Emanuel F. Petricoin III Ph.D.

  2. Virginia Cancer Specialists, 8503 Arlington Blvd, Suite 400, Fairfax, VA, 22031, USA

    Alexander Spira M.D.

  3. Department of Surgery, Inova Fairfax Hospital Cancer Center, 3300 Gallows Road, Falls Church, VA, 22042, USA

    Alexander Spira M.D. & Kirsten H. Edmiston M.D., F.A.C.S.

Authors
  1. Julia D. Wulfkuhle Ph.D.
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  2. Alexander Spira M.D.
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  3. Kirsten H. Edmiston M.D., F.A.C.S.
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  4. Emanuel F. Petricoin III Ph.D.
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Corresponding author

Correspondence to Julia D. Wulfkuhle Ph.D. .

Editor information

Editors and Affiliations

  1. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, USA

    Virginia Espina

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Wulfkuhle, J.D., Spira, A., Edmiston, K.H., Petricoin, E.F. (2017). Innovations in Clinical Trial Design in the Era of Molecular Profiling. In: Espina, V. (eds) Molecular Profiling. Methods in Molecular Biology, vol 1606. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6990-6_2

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  • DOI: https://doi.org/10.1007/978-1-4939-6990-6_2

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6989-0

  • Online ISBN: 978-1-4939-6990-6

  • eBook Packages: Springer Protocols

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