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  • Perspective
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OPINION

Phase I trials as valid therapeutic options for patients with cancer

Nature Reviews Clinical Oncology volume 16, pages 773–778 (2019)Cite this article

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Abstract

For many years, oncology phase I trials have been referred to as ‘toxicity trials’ and have been believed to have low clinical utility other than that of establishing the adverse event profile of novel therapeutic agents. The traditional distinction of clinical trials into three phases has been challenged in the past few years by the introduction of targeted therapies and immunotherapies into the routine management of patients with cancer. This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly reported from phase I trials. In this Perspectives, we highlight key elements of phase I trials and discuss how each one of them contributes to a new paradigm whereby preliminary measurements of the clinical benefit from a novel treatment can be obtained in current phase I trials, which can therefore be considered to have a therapeutic intent.

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Fig. 1: Phase I trials as valid therapeutic options.

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References

  1. Storer, B. E. Design and analysis of phase I clinical trials. Biometrics 45, 925–937 (1989).

    CAS  PubMed  Google Scholar 

  2. Simon, R. Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 10, 1–10 (1989).

    CAS  PubMed  Google Scholar 

  3. Carter, S. K. Clinical trials in cancer chemotherapy. Cancer 40, 544–557 (1977).

    CAS  PubMed  Google Scholar 

  4. Cook, N. et al. Early phase clinical trials to identify optimal dosing and safety. Mol. Oncol. 9, 997–1007 (2015).

    CAS  PubMed  Google Scholar 

  5. Manji, A. et al. Evolution of clinical trial design in early drug development: systematic review of expansion cohort use in single-agent phase I cancer trials. J. Clin. Oncol. 31, 4260–4267 (2013).

    CAS  PubMed  Google Scholar 

  6. Postel-Vinay, S. & Soria, J. C. Phase I trials in oncology: a new era has started. Ann. Oncol. 26, 7–9 (2015).

    CAS  PubMed  Google Scholar 

  7. Chabner, B. A. Approval after phase I: ceritinib runs the three-minute mile. Oncologist 19, 577–578 (2014).

    PubMed  PubMed Central  Google Scholar 

  8. Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chuk, M. K. et al. FDA approval summary: accelerated approval of pembrolizumab for second-line treatment of metastatic melanoma. Clin Cancer Res 23, 5666–5670 (2017).

    CAS  PubMed  Google Scholar 

  10. Chen, C. et al. Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann. Oncol. 28, 1388–1398 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Kimmelman, J. Is participation in cancer phase I trials really therapeutic? J. Clin. Oncol. 35, 135–138 (2017).

    PubMed  Google Scholar 

  12. Agrawal, M. & Emanuel, E. J. Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 290, 1075–1082 (2003).

    PubMed  Google Scholar 

  13. Estey, E. et al. Therapeutic response in phase I trials of antineoplastic agents. Cancer Treat. Rep. 70, 1105–1115 (1986).

    CAS  PubMed  Google Scholar 

  14. Decoster, G., Stein, G. & Holdener, E. E. Responses and toxic deaths in phase I clinical trials. Ann. Oncol. 1, 175–181 (1990).

    CAS  PubMed  Google Scholar 

  15. Horstmann, E. et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N. Engl. J. Med. 352, 895–904 (2005).

    CAS  PubMed  Google Scholar 

  16. Roberts, T. G. Jr. et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292, 2130–2140 (2004).

    CAS  PubMed  Google Scholar 

  17. Schwaederle, M. et al. Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. JAMA Oncol. 2, 1452–1459 (2016).

    PubMed  Google Scholar 

  18. Waligora, M. et al. Risk and surrogate benefit for pediatric phase I trials in oncology: a systematic review with meta-analysis. PLoS Med. 15, e1002505 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. Chakiba, C. et al. Encouraging trends in modern phase 1 oncology trials. N. Engl. J. Med. 378, 2242–2243 (2018).

    PubMed  Google Scholar 

  20. Oxnard, G. R. et al. Response rate as a regulatory end point in single-arm studies of advanced solid tumors. JAMA. Oncol. 2, 772–779 (2016).

    Google Scholar 

  21. Kurzrock, R. & Benjamin, R. S. Risks and benefits of phase 1 oncology trials, revisited. N. Engl. J. Med. 352, 930–932 (2005).

    CAS  PubMed  Google Scholar 

  22. Weber, J. S. et al. American Society of Clinical Oncology policy statement update: the critical role of phase I trials in cancer research and treatment. J. Clin. Oncol. 33, 278–284 (2015).

    PubMed  Google Scholar 

  23. Miller, F. G. & Joffe, S. Phase 1 oncology trials and informed consent. J. Med. Ethics 39, 761–764 (2013).

    PubMed  Google Scholar 

  24. Saad, E. D. et al. Precision medicine needs randomized clinical trials. Nat. Rev. Clin. Oncol. 14, 317–323 (2017).

    PubMed  Google Scholar 

  25. Weber, J. S. et al. Reaffirming and clarifying the American Society of Clinical Oncology’s policy statement on the critical role of phase I trials in cancer research and treatment. J. Clin. Oncol. 35, 139–140 (2017).

    PubMed  Google Scholar 

  26. Grunwald, H. W. Ethical and design issues of phase I clinical trials in cancer patients. Cancer Invest. 25, 124–126 (2007).

    PubMed  Google Scholar 

  27. Chvetzoff, G. & Tannock, I. F. Placebo effects in oncology. J. Natl Cancer Inst. 95, 19–29 (2003).

    CAS  PubMed  Google Scholar 

  28. Jardim, D. L. et al. Factors associated with failure of oncology drugs in late-stage clinical development: a systematic review. Cancer Treat. Rev. 52, 12–21 (2017).

    PubMed  Google Scholar 

  29. Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

    CAS  PubMed  Google Scholar 

  30. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Okamura, R. et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis. Oncol. https://doi.org/10.1200/PO.18.00183 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mangat, P. K. et al. Rationale and design of the targeted agent and profiling utilization registry study. JCO Precis. Oncol. https://doi.org/10.1200/PO.18.00122 (2018).

    Article  Google Scholar 

  33. Severson, T. M. et al. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res. 19, 99 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. Asakawa, T., Hirakawa, A. & Hamada, C. Bayesian model averaging continual reassessment method for bivariate binary efficacy and toxicity outcomes in phase I oncology trials. J. Biopharm. Stat. 24, 310–325 (2014).

    PubMed  Google Scholar 

  35. Sicklick, J. K. et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat. Med. 25, 744–750 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zia, M. I. et al. Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J. Clin. Oncol. 23, 6982–6991 (2005).

    CAS  PubMed  Google Scholar 

  37. De Ridder, F. Predicting the outcome of phase III trials using phase II data: a case study of clinical trial simulation in late stage drug development. Basic Clin. Pharmacol. Toxicol. 96, 235–241 (2005).

    PubMed  Google Scholar 

  38. Kurzrock, R. & Stewart, D. J. Equipoise abandoned? Randomization and clinical trials. Ann. Oncol. 24, 2471–2474 (2013).

    CAS  PubMed  Google Scholar 

  39. Johnson, K. R. et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet Oncol. 7, 741–746 (2006).

    PubMed  Google Scholar 

  40. Buyse, M. et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356, 373–378 (2000).

    CAS  PubMed  Google Scholar 

  41. Burzykowski, T. et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J. Clin. Oncol. 26, 1987–1992 (2008).

    CAS  PubMed  Google Scholar 

  42. Blumenthal, G. M. et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J. Clin. Oncol. 33, 1008–1014 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. Tsimberidou, A. M. et al. Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J. Clin. Oncol. 27, 6243–6250 (2009).

    CAS  PubMed  Google Scholar 

  44. Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 18, e143–e152 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. Jensen, T. J. et al. Genome-wide sequencing of cell-free DNA identifies copy-number alterations that can be used for monitoring response to immunotherapy in cancer patients. Mol. Cancer Ther. 18, 448–458 (2019).

    CAS  PubMed  Google Scholar 

  46. Rothwell, D. G. et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat. Med. 25, 738–743 (2019).

    CAS  PubMed  Google Scholar 

  47. Cohen-Kurzrock, B. A., Cohen, P. R. & Kurzrock, R. Health policy: the right to try is embodied in the right to die. Nat. Rev. Clin. Oncol. 13, 399–400 (2016).

    CAS  PubMed  Google Scholar 

  48. US Congress S.204 - Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 Congress.gov https://www.congress.gov/bill/115th-congress/senate-bill/204/text (2018).

  49. Puthumana, J., Miller, J. E., Kim, J. & Ross, J. S. Availability of investigational medicines through the US Food and Drug Administration’s expanded access and compassionate use programs. JAMA Netw. Open 1, e180283 (2018).

    PubMed  PubMed Central  Google Scholar 

  50. Feit, N. Z. et al. Use, safety, and efficacy of single-patient use of the US Food and Drug Administration expanded access program. JAMA Oncol 5, 570–572 (2019).

    PubMed  PubMed Central  Google Scholar 

  51. Rosenfeld, E. H. et al. Use of standardized visual aids improves informed consent for appendectomy in children: a randomized control trial. Am. J. Surg. 216, 730–735 (2018).

    PubMed  Google Scholar 

  52. Lim, C. Patients with advanced non-small cell lung cancer: are research biopsies a barrier to participation in clinical trials? J. Thorac. Oncol. 11, 79–84 (2016).

    PubMed  Google Scholar 

  53. Prasad, V. & Goldstein, J. A. Clinical trial spots for cancer patients by tumour type: the cancer trials portfolio at clinicaltrials.gov. Eur. J. Cancer 51, 2718–2723 (2015).

    PubMed  PubMed Central  Google Scholar 

  54. Recondo, G. et al. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat. Rev. Clin. Oncol. 15, 694–708 (2018).

    CAS  PubMed  Google Scholar 

  55. Herbst, R. S. et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J. Clin. Oncol. 20, 3815–3825 (2002).

    CAS  PubMed  Google Scholar 

  56. Drilon, A. E. et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J. Clin. Oncol. 36, 102–102 (2018).

    Google Scholar 

  57. Piotrowska, Z. et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and blu-667 for acquired RET fusion. Cancer Discov. 8, 1529–1539 (2018).

    PubMed  PubMed Central  Google Scholar 

  58. Jardim, D. L. et al. Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs. Clin. Cancer Res. 20, 281–288 (2014).

    CAS  PubMed  Google Scholar 

  59. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    CAS  PubMed  Google Scholar 

  60. Costa, R. et al. Analyses of selected safety endpoints in phase 1 and late-phase clinical trials of anti-PD-1 and PD-L1 inhibitors: prediction of immune-related toxicities. Oncotarget 8, 67782–67789 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. Chhabra, P., Chen, X. & Weiss, S. R. Adverse event reporting patterns of newly approved drugs in the USA in 2006: an analysis of FDA Adverse Event Reporting System data. Drug Saf. 36, 1117–1123 (2013).

    CAS  PubMed  Google Scholar 

  62. Gliklich R. E., Dreyer N. A., Leavy M. B. Registries for evaluating patient outcomes: a user’s guide (ed 3rd). (Agency for Healthcare Research and Quality, 2014).

  63. Jain, R. K. et al. Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse. Clin. Cancer Res. 16, 1289–1297 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gupta, S. et al. Meta-analysis of the relationship between dose and benefit in phase I targeted agent trials. J. Natl Cancer Inst. 104, 1860–1866 (2012).

    CAS  PubMed  Google Scholar 

  65. Le Tourneau, C., Lee, J. J. & Siu, L. L. Dose escalation methods in phase I cancer clinical trials. J. Natl Cancer Inst. 101, 708–720 (2009).

    PubMed  PubMed Central  Google Scholar 

  66. Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    CAS  PubMed  Google Scholar 

  67. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Dolly, S. O. et al. A study of motivations and expectations of patients seen in phase 1 oncology clinics. Cancer 122, 3501–3508 (2016).

    PubMed  Google Scholar 

  70. Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    CAS  PubMed  Google Scholar 

  71. Wheler, J. et al. Survival of patients in a phase 1 clinic: the M. D. Anderson Cancer Center experience. Cancer 115, 1091–1099 (2009).

    PubMed  Google Scholar 

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Acknowledgements

The work of R.K. is funded in part by the Joan and Irwin Jacobs Fund and NIH P30 grant CA023100.

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Authors and Affiliations

  1. Department of Internal Medicine, University of South Florida, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Jacob J. Adashek

  2. Early Therapeutics Program, Yale Cancer Center, New Haven, CT, USA

    Patricia M. LoRusso

  3. Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    David S. Hong

  4. Center for Personalized Cancer Therapy, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA

    Razelle Kurzrock

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  3. David S. Hong
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J.J.A. and R.K. researched data for the article, discussed the article contents and wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Razelle Kurzrock.

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Competing interests

P.M.L. is an advisory board member for Agenus, Cyrexa, CytomX and Genentech; a data safety monitoring board or committee member for Agios, FivePrime and Halozyme; an imCORE Alliance member for Roche; and a consultant for SOTIO. D.S.H. receives research and/or grant support from AbbVie, Adaptimmune, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI–CTEP, Novartis, Pfizer, Seattle Genetics and Takeda; travel and accommodation support from AACR, ASCO, Genmab, LOXO, MiRNA and SITC; is a consultant or adviser for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Molecular Match, Numab, Presagia, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics and WebMD; and is a founder of OncoResponse. R.K. owns stock and has other equity interests in CureMatch, IDbyDNA and Soluventis; is a consultant or adviser for Actuate Therapeutic, Gaido, LOXO, NeoMed, Roche, Soluventis and X-Biotech; has received speaker’s fees from Roche; is a board member of CureMatch; and her institution receives research support from Foundation Medicine, Genentech, Grifols, Guardant Health, Incyte, Konica Minolta Merck Serono, OmniSeq, Pfizer and Sequenom. J.J.A. declares no competing interests.

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P.M.L., D.S.H. and R.K. have developed their medical career as experts in phase I trials.

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Adashek, J.J., LoRusso, P.M., Hong, D.S. et al. Phase I trials as valid therapeutic options for patients with cancer. Nat Rev Clin Oncol 16, 773–778 (2019). https://doi.org/10.1038/s41571-019-0262-9

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