The changing landscape of phase I trials in oncology

Nature Reviews Clinical Oncology

Volumn 13, Issue 2, 2016, Pages 106-117

  Wong, Kit Man ^a   Capasso, Anna ^a   Eckhardt, S Gail ^a  

^a UNIVERSITY OF COLORADO CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALECTINIB; ANTINEOPLASTIC AGENT; ATEZOLIZUMAB; BEVACIZUMAB; CARBOPLATIN; CERITINIB; CRIZOTINIB; DURVALUMAB; FLUOROURACIL; FOLINIC ACID; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MOLECULARLY TARGETED AGENT; NIVOLUMAB; OXALIPLATIN; PACLITAXEL; PEMETREXED; PHOSPHATIDYLINOSITOL 3 KINASE; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN KINASE B; PROTEIN TYROSINE KINASE INHIBITOR; RAF PROTEIN; TRAMETINIB; UNCLASSIFIED DRUG; VEMURAFENIB;

CANCER RESEARCH; COLORECTAL CANCER; DIARRHEA; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG RESPONSE; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; FATIGUE; HUMAN; KIDNEY CARCINOMA; MELANOMA; MOLECULARLY TARGETED THERAPY; NON SMALL CELL LUNG CANCER; OVARY CANCER; PATIENT SELECTION; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RASH; REVIEW; STOMACH CANCER; STUDY DESIGN; TRIPLE NEGATIVE BREAST CANCER; DOSE RESPONSE; MAXIMUM TOLERATED DOSE; METHODOLOGY; NEOPLASMS; PROCEDURES; TRENDS;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE I AS TOPIC; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MAXIMUM TOLERATED DOSE; NEOPLASMS; RESEARCH DESIGN;

EID: 84955661100     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2015.194     Document Type: Review

References (139)

1. American Cancer Society Cancer Facts and Figures 2015 [online], http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/index (2015).
2. Euhus, D., Di Carlo, P. A., & Khouri, N. F. Breast cancer screening. Surg. Clin. North Am. 95, 991-1011 (2015).
3. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395-409 (2011).
4. Rajput, A., & Bullard Dunn, K. Surgical management of rectal cancer. Semin. Oncol. 34, 241-249 (2007).
5. Van Gijn, W., et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12 year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 12, 575-582 (2011).
6. Pharmaceutical Research and Manufacturers of America Medicines in Development: Cancer [Online], Http://www.phrma.org/sites/default/files/pdf/2014 2014-cancer-report.pdf
7. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C., & Rosenthal, J. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40-51 (2014).
8. Pharmaceutical Research and Manufacturers of America Researching Cancer Medicines: Setbacks and Stepping Stones [Online], Http://www.phrma.org/sites/default/files/pdf/2014-cancer-failures-setbacks.pdf (2014).
9. DiMasi, J. A., & Grabowski, H. G. Economics of new oncology drug development. J. Clin. Oncol. 25, 209-216 (2007).
10. Le Tourneau, C., Stathis, A., Vidal, L., Moore, M. J., & Siu, L. L. Choice of starting dose for molecularly targeted agents evaluated in first in human phase I cancer clinical trials. J. Clin. Oncol. 28, 1401-1407 (2010).
11. Ivy, S. P., Siu, L. L., 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. 16, 1726-1736 (2010).
12. 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).
13. LoRusso, P. M., Boerner, S. A., & Seymour, L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin. Cancer Res. 16, 1710-1718 (2010).
14. Mick, R., & Ratain, M. J. Model-guided determination of maximum tolerated dose in phase I clinical trials: evidence for increased precision. J. Natl Cancer Inst. 85, 217-223 (1993).
15. Dowlati, A., et al. Multi-institutional phase I trials of anticancer agents. J. Clin. Oncol. 26, 1926-1931 (2008).
16. Postel-Vinay, S., et al. Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents ' dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study. Eur. J. Cancer 50, 2040-2049 (2014).
17. Le Tourneau, C., et al. Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: a review of the literature. Eur. J. Cancer 47, 1468-1475 (2011).
18. Paoletti, X., et al. Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: results of a DLT-TARGETT international survey. Eur. J. Cancer 50, 2050-2056 (2014).
19. Adamina, M., & Joerger, M. Dose-Toxicity models in oncology. Expert Opin. Drug Metab. Toxicol. 7, 201-211 (2011).
20. Simon, R., et al. Accelerated titration designs for phase I clinical trials in oncology. J. Natl Cancer Inst. 89, 1138-1147 (1997).
21. Penel, N., et al. "Classical 3 + 3 design" versus "accelerated titration designs": analysis of 270 phase 1 trials investigating anti-cancer agents. Invest. New Drugs 27, 552-556 (2009).
22. Dancey, J., Freidlin, B., & Rubinstein, L. in Statistical methods for dose-finding experiments ed. Chevret, S.) 91 (Wiley Press, 2006).
23. Skolnik, J. M., Barrett, J. S., Jayaraman, B., Patel, D., & Adamson, P. C. Shortening the timeline of pediatric phase I trials: the rolling six design. J. Clin. Oncol. 26, 190-195 (2008).
24. Onar-Thomas, A., & Xiong, Z. A simulation-based comparison of the traditional method, Rolling 6 design and a frequentist version of the continual reassessment method with special attention to trial duration in pediatric phase I oncology trials. Contemp. Clin. Trials 31, 259-270 (2010).
25. Doussau, A., et al. Dose-finding designs in pediatric phase I clinical trials: comparison by simulations in a realistic timeline framework. Contemp. Clin. Trials 33, 657-665 (2012).
26. Sposto, R., & Groshen, S. A wide-spectrum paired comparison of the properties of the Rolling 6 and 3+3 Phase I study designs. Contemp. Clin. Trials 32, 694-703 (2011).
27. O'Quigley, J., Pepe, M., & Fisher, L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46, 33-48 (1990).
28. Iasonos, A., Zohar, S., & O'Quigley, J. Incorporating lower grade toxicity information into dose finding designs. Clin. Trials 8, 370-379 (2011).
29. Yuan, Z., Chappell, R., & Bailey, H. The continual reassessment method for multiple toxicity grades: a Bayesian quasi-likelihood approach. Biometrics 63, 173-179 (2007).
30. Ezzalfani, M., Zohar, S., Qin, R., Mandrekar, S. J., & Deley, M. C. Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities. Stat Med. 32, 2728-2746 (2013).
31. Van Meter, E. M., Garrett-Mayer, E., & Bandyopadhyay, D. Proportional odds model for dose-finding clinical trial designs with ordinal toxicity grading. Stat. Med. 30, 2070-2080 (2011).
32. Van Meter, E. M., Garrett-Mayer, E., & Bandyopadhyay, D. Dose-finding clinical trial design for ordinal toxicity grades using the continuation ratio model: an extension of the continual reassessment method. Clin. Trials 9, 303-313 (2012).
33. Goodman, S. N., Zahurak, M. L., & Piantadosi, S. Some practical improvements in the continual reassessment method for phase I studies. Stat. Med. 14, 1149-1161 (1995).
34. Piantadosi, S., Fisher, J. D., & Grossman, S. Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother. Pharmacol. 41, 429-436 (1998).
35. Rogatko, A., Babb, J. S., Tighiouart, M., Khuri, F. R., & Hudes, G. New paradigm in dose-finding trials: patient-specific dosing and beyond phase I. Clin. Cancer Res. 11, 5342-5346 (2005).
36. O'Quigley, J., & Shen, L. Z. Continual reassessment method: a likelihood approach. Biometrics 52, 673-684 (1996).
37. Cheung, Y. K., & Chappell, R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 56, 1177-1182 (2000).
38. O'Quigley, J., & Conaway, M. Extended model-based designs for more complex dose-finding studies. Stat. Med. 30, 2062-2069 (2011).
39. Zhang, W., Sargent, D. J., & Mandrekar, S. An adaptive dose-finding design incorporating both toxicity and efficacy. Stat. Med. 25, 2365-2383 (2006).
40. Thall, P. F., & Cook, J. D. Dose-finding based on efficacy-Toxicity trade-offs. Biometrics 60, 684-693 (2004).
41. Thall, P. F., Cook, J. D & Estey, E. H. Adaptive dose selection using efficacy-Toxicity trade-offs: illustrations and practical considerations. J. Biopharm. Stat. 16, 623-638 (2006).
42. Mandrekar, S. J., Qin, R., & Sargent, D. J. Model-based phase I designs incorporating toxicity and efficacy for single and dual agent drug combinations: methods and challenges. Stat. Med. 29, 1077-1083 (2010).
43. Le Tourneau, C., Gan, H. K., Razak, A. R., & Paoletti, X. Efficiency of new dose escalation designs in dose-finding phase I trials of molecularly targeted agents. PLoS ONE 7, e51039 (2012).
44. Jaki, T., Clive, S., & Weir, C. J. Principles of dose finding studies in cancer: a comparison of trial designs. Cancer Chemother. Pharmacol. 71, 1107-1114 (2013).
45. Rogatko, A., et al. Translation of innovative designs into phase I trials. J. Clin. Oncol. 25, 4982-4986 (2007).
46. Wood, L. D., et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113 (2007).
47. Wong, K. M., Hudson, T. J., & McPherson, J. D. Unraveling the genetics of cancer: genome sequencing and beyond. Annu. Rev. Genomics Hum. Genet. 12, 407-430 (2011).
48. Gerdes, M. J., et al. Emerging understanding of multiscale tumor heterogeneity. Front. Oncol. 4, 366 (2014).
49. Ludwig, J. A., & Weinstein, J. N. Biomarkers in cancer staging, prognosis and treatment selection. Nat. Rev. Cancer 5, 845-856 (2005).
50. Henry, N. L., & Hayes, D. F. Cancer biomarkers. Mol. Oncol. 6, 140-146 (2012).
51. Gonzalez De Castro, D., Clarke, P. A., Al-Lazikani, B., & Workman, P. Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. Clin. Pharmacol. Ther. 93, 252-259 (2013).
52. Hollebecque, A., et al. Modifying phase I methodology to facilitate enrolment of molecularly selected patients. Eur. J. Cancer 49, 1515-1520 (2013).
53. Kwak, E. L., et al. Anaplastic lymphoma kinase inhibition in non small cell lung cancer. N. Engl. J. Med. 363, 1693-1703 (2010).
54. Shaw, A. T., et al. Ceritinib in ALK-rearranged non small cell lung cancer. N. Engl. J. Med. 370, 1189-1197 (2014).
55. Seto, T., et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non small cell lung cancer (AF 001JP study): a single-Arm, open-label, phase 1-2 study. Lancet Oncol. 14, 590-598 (2013).
56. Flaherty, K. T., et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809-819 (2010).
57. Dancey, J. E., et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin. Cancer Res. 16, 1745-1755 (2010).
58. [No authors listed] 2012 best practices for repositories collection, storage, retrieval, and distribution of biological materials for research international society for biological and environmental repositories. Biopreserv. Biobank. 10, 79-161 (2012).
59. Chau, C. H., Rixe, O., McLeod, H., & Figg, W. D. Validation of analytic methods for biomarkers used in drug development. Clin. Cancer Res. 14, 5967-5976 (2008).
60. Wagner, J. A. Strategic approach to fit for purpose biomarkers in drug development. Annu. Rev. Pharmacol. Toxicol. 48, 631-651 (2008).
61. 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).
62. Falchook, G. S., et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 13, 782-789 (2012).
63. Rodon, J., et al. Molecular prescreening to select patient population in early clinical trials. Nat. Rev. Clin. Oncol. 9, 359-366 (2012).
64. 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).
65. Bugano, D., et al. Impact of phase 1 expansion cohorts on probability of success in phase 2 and time to drug-Approval: analysis of 385 new drugs in oncology [abstract 237]. Eur. J. Cancer 50, 79-80 (2014).
66. Shea, M. B., Roberts, S. A., Walrath, J. C., Allen, J. D., & Sigal, E. V. Use of multiple endpoints and approval paths depicts a decade of FDA oncology drug approvals. Clin. Cancer Res. 19, 3722-3731 (2013).
67. Garon, E. B., et al. Pembrolizumab for the treatment of non small cell lung cancer. N. Engl. J. Med. 372, 2018-2028 (2015).
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).
69. Robert, C., et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320-330 (2015).
70. Weber, J. S., et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti CTLA 4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375-384 (2015).
71. Lee, S. M., & Chow, L. Q. A new addition to the PD 1 checkpoint inhibitors for non-small cell lung cancer-The anti PDL1 antibody MEDI4736. Transl. Lung Cancer Res. 3, 408-410 (2014).
72. Parulekar, W. R., & Eisenhauer, E. A. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J. Natl Cancer Inst. 96, 990-997 (2004).
73. 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).
74. Postel-Vinay, S., et al. Clinical benefit in phase I trials of novel molecularly targeted agents: does dose matter?. Br. J. Cancer 100, 1373-1378 (2009).
75. 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).
76. Dienstmann, R., Brana, I., Rodon, J., & Tabernero, J. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist 16, 1729-1740 (2011).
77. Widakowich, C., De Castro, G. Jr, De Azambuja, E., Dinh, P., & Awada, A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist 12, 1443-1455 (2007).
78. Dy, G. K., & Adjei, A. A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J. Clin. 63, 249-279 (2013).
79. De Castro, G. Jr & Awada, A. Side effects of anti-cancer molecular-Targeted therapies (not monoclonal antibodies). Curr. Opin. Oncol. 18, 307-315 (2006).
80. Lynch, T. J. Jr et al. Epidermal growth factor receptor inhibitor-Associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12, 610-621 (2007).
81. Loriot, Y., et al. Drug insight: gastrointestinal and hepatic adverse effects of molecular-Targeted agents in cancer therapy. Nat. Clin. Pract. Oncol. 5, 268-278 (2008).
82. Eaby, B., Culkin, A., & Lacouture, M. E. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin. J. Oncol. Nurs. 12, 283-290 (2008).
83. Grothey, A. Recognizing and managing toxicities of molecular targeted therapies for colorectal cancer. Oncology (Williston Park) 20, 21-28 (2006).
84. Workman, P., et al. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-Testing clinical trials of innovative therapies. J. Natl Cancer Inst. 98, 580-598 (2006).
85. Lorente, D., Mateo, J., & De Bono, J. S. Molecular characterization and clinical utility of circulating tumor cells in the treatment of prostate cancer. Am. Soc. Clin. Oncol. Educ. Book 2014, e197-e203 (2014).
86. Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579-586 (2014).
87. Comets, E., & Zohar, S. A survey of the way pharmacokinetics are reported in published phase I clinical trials, with an emphasis on oncology. Clin. Pharmacokinet. 48, 387-395 (2009).
88. Goulart, B. H., et al. Trends in the use and role of biomarkers in phase I oncology trials. Clin. Cancer Res. 13, 6719-6726 (2007).
89. Duffy, M. J., et al. Validation of new cancer biomarkers: a position statement from the European group on tumor markers. Clin. Chem. 61, 809-820 (2015).
90. Josephs, D., Spicer, J., & O'Doherty, M. Molecular imaging in clinical trials. Target Oncol. 4, 151-168 (2009).
91. Stephen, R. M., & Gillies, R. J. Promise and progress for functional and molecular imaging of response to targeted therapies. Pharm. Res. 24, 1172-1185 (2007).
92. Meric-Bernstam, F., & Mills, G. B. Overcoming implementation challenges of personalized cancer therapy. Nat. Rev. Clin. Oncol. 9, 542-548 (2012).
93. Hagemann, I. S., Cottrell, C. E., & Lockwood, C. M. Design of targeted, capture-based, next generation sequencing tests for precision cancer therapy. Cancer Genet. 206, 420-431 (2013).
94. Andre, F., et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 15, 267-274 (2014).
95. Weiss G J., et al. A pilot study using next-generation sequencing in advanced cancers: feasibility and challenges. PLoS ONE e76438 (2013).
96. Janku, F., Kaseb, A. O., Tsimberidou, A. M., Wolff, R. A., & Kurzrock, R. Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget 5, 3012-3022 (2014).
97. Dienstmann, R., et al. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. Mol. Cancer Ther. 11, 2062-2071 (2012).
98. Tuxen, I. V., et al. Personalized oncology: genomic screening in phase 1. APMIS 122, 723-733 (2014).
99. Tsimberidou, A. M., et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin. Cancer Res. 18, 6373-6383 (2012).
100. Le Tourneau, C., et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase http://dx.doi.org/10.1016/S1470-2045(15)00188-6
101. Schwaederle, M., et al. Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. Oncologist 19, 631-636 (2014).
102. Cronin, M., & Ross, J. S. Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark. Med. 5, 293-305 (2011).
103. Crockford, A., Jamal-Hanjani, M., Hicks, J., & Swanton, C. Implications of intratumour heterogeneity for treatment stratification. J. Pathol. 232, 264-273 (2014).
104. Xuan, J., Yu, Y., Qing, T., Guo, L., & Shi, L. Next-generation sequencing in the clinic: promises and challenges. Cancer Lett. 340, 284-295 (2013).
105. Kruglyak, K. M., Lin, E., & Ong, F. S. Next-generation sequencing in precision oncology: challenges and opportunities. Expert Rev. Mol. Diagn. 14, 635-637 (2014).
106. McNeil, C. NCI-MATCH launch highlights new trial design in precision-medicine era. J. Natl Cancer Inst. 107, djv193 (2015).
107. National Cancer Institute. NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) Trial [online] http://www.cancer.gov/about-cancer/treatment/clinical-Trials/nci-supported/nci-match (2015).
108. Roychowdhury, S., et al. Personalized oncology through integrative high-Throughput sequencing: a pilot study. Sci. Transl. Med. 3, 111ra121 (2011).
109. Meric-Bernstam, F., Farhangfar, C., Mendelsohn, J., & Mills, G. B. Building a personalized medicine infrastructure at a major cancer center. J. Clin. Oncol. 31, 1849-1857 (2013).
110. Ocana, A., Freedman, O., Amir, E., Seruga, B., & Pandiella, A. Biological insights into effective and antagonistic combinations of targeted agents with chemotherapy in solid tumors. Cancer Metastasis Rev. 33, 295-307 (2014).
111. Jia, J., et al. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov. 8, 111-128 (2009).
112. Reinhardt, H. C., Jiang, H., Hemann, M. T., & Yaffe, M. B. Exploiting synthetic lethal interactions for targeted cancer therapy. Cell Cycle 8, 3112-3119 (2009).
113. Paller, C. J., et al. Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee. Clin. Cancer Res. 20, 4210-4217 (2014).
114. US National Library of Medicine ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01633970?term=NCT01633970&rank=1 (2015).
115. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02423954?term=NCT02423954&rank=1 (2015).
116. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01454102?term=NCT01454102&rank=1 (2015).
117. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02039674?term=NCT02039674&rank=1 (2015).
118. Cha, E., Wallin, J., & Kowanetz, M. PD L1 inhibition with MPDL3280A for solid tumors. Semin. Oncol. 42, 484-487 (2015).
119. Riviere, M. K., Dubois, F., & Zohar, S. Competing designs for drug combination in phase I dose-finding clinical trials. Stat. Med. 34, 1-12 (2015).
120. Riviere, M. K., Le Tourneau, C., Paoletti, X., Dubois, F., & Zohar, S. Designs of drug-combination phase I trials in oncology: a systematic review of the literature. Ann. Oncol. 26, 669-674 (2015).
121. Hamberg, P., Ratain, M. J., Lesaffre, E., & Verweij, J. Dose-escalation models for combination phase I trials in oncology. Eur. J. Cancer 46, 2870-2878 (2010).
122. Harrington, J. A., Wheeler, G. M., Sweeting, M. J., Mander, A. P., & Jodrell, D. I. Adaptive designs for dual-Agent phase I dose-escalation studies. Nat. Rev. Clin. Oncol. 10, 277-288 (2013).
123. Mandrekar, S. J. Dose-finding trial designs for combination therapies in oncology. J. Clin. Oncol. 32, 65-67 (2014).
124. Cannistra, S. A. Challenges and pitfalls of combining targeted agents in phase I studies. J. Clin. Oncol. 26, 3665-3667 (2008).
125. Dancey, J. E., & Chen, H. X. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat. Rev. Drug Discov. 5, 649-659 (2006).
126. Kummar, S., et al. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat. Rev. Drug Discov. 9, 843-856 (2010).
127. Pollyea, D. A., et al. Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 26, 893-901 (2012).
128. Yoshioka, T., et al. Phase I/II study of sequential therapy with irinotecan and S 1 for metastatic colorectal cancer. Br. J. Cancer 101, 1972-1977 (2009).
129. Bruce, J. Y., et al. A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies. Cancer Chemother. Pharmacol. 73, 485-493 (2014).
130. Sherman, R. E., Li, J., Shapley, S., Robb, M., & Woodcock, J. Expediting drug development ' the FDA's new "breakthrough therapy" designation. N. Engl. J. Med. 369, 1877-1880 (2013).
131. Pignatti, F., Jonsson, B., Blumenthal, G., & Justice, R. Assessment of benefits and risks in development of targeted therapies for cancer ' the view of regulatory authorities. Mol. Oncol. 9, 1034-1041 (2015).
132. US Food and Drug Administration Food and Drug Administration, Regulatory Information, Food and Drug Administration Safety and Innovation Act (FDASIA) [Online], Http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm (2015).
133. Kramer, D. B., & Kesselheim, A. S. User fees and beyond ' the FDA Safety and Innovation Act of 2012. N. Engl. J. Med. 367, 1277-1279 (2012).
134. US Food and Drug Administration Guidance for Industry Expedited Programs for Serious Conditions ' Drugs and Biologics [online], http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory information/guidances/ucm358301.pdf (2014).
135. Kesselheim, A. S., & Darrow, J. J. FDA designations for therapeutics and their impact on drug development and regulatory review outcomes. Clin. Pharmacol. Ther. 97, 29-36 (2015).
136. US Food and Drug Administration Breakthrough Therapy Approvals [Online], Http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeveloped AndApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm373418.htm (2015).
137. Gadgeel, S. M., et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non small cell lung cancer (AF 002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 15, 1119-1128 (2014).
138. Khozin, S., et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin. Cancer Res. 21, 2436-2439 (2015).
139. Wong, K. M., Noonan, S., O'Bryant, C., & Jimeno, A. Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer. Drugs Today (Barc.) 51, 161-170 (2015).