The changing landscape of phase i trials in oncology

KEY POINTS * Several aspects of the design of phase I trials have evolved in the era of molecular targeted agents to enable better assessment of these novel therapies and maximize the

efficiency of drug development * Current phase I trial designs increasingly use new dose-escalation approaches and biomarker-driven patient selection, while expanding study objectives to

include efficacy evaluation and pharmacokinetics/ pharmacodynamics (PK/PD), in addition to safety * Preclinical evidence supporting a biological or pharmacological rationale and exploration

of PK/PD interactions between drug partners are necessary for phase I trials of combination therapies that include targeted agents * Changes to the regulatory approval process help to

expedite drug development, particularly for novel agents with a well-established biological mechanism, a predictive biomarker, and clear evidence of efficacy in early trials * Changes in the

goals and conduct of phase I trials have resulted in a shift towards multi-institutional studies and centralized management, with a significant impact on the structure of phase I programmes

* Both the efficiency and rate of drug approval need to improve despite the limited acceptance of novel trial designs and difficulties associated with early phase biomarker integration

ABSTRACT Advances in our knowledge of the molecular pathogenesis of cancer have led to increased interest in molecularly targeted agents (MTAs), which target specific oncogenic drivers and

are now a major focus of cancer drug development. MTAs differ from traditional cytotoxic agents in various aspects, including their toxicity profiles and the potential availability of

predictive biomarkers of response. The landscape of phase I oncology trials is evolving to adapt to these novel therapies and to improve the efficiency of drug development. In this Review,

we discuss new strategies used in phase I trial design, such as novel dose-escalation schemes to circumvent limitations of the classic 3 + 3 design and enable faster dose escalation and/or

more-precise dose determinations using statistical modelling; improved selection of patients based on genetic or molecular biomarkers; pharmacokinetic and pharmacodynamic analyses; and the

early evaluation of efficacy — in addition to safety. Indeed, new expedited approval pathways that can accelerate drug development require demonstration of efficacy in early phase trials.

The application of molecular tumour profiling for matched therapy and the testing of drug combinations based on a strong biological rationale are also increasingly seen in phase I studies.

Finally, the shift towards multi-institutional trials and centralized study management results in consequent implications for institutions and investigators. These issues are also

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CTDNA-BASED EVIDENCE OF RECURRENCE Article 30 September 2024 REFERENCES * American Cancer Society. _Cancer Facts and Figures 2015_ [online], (2015). * Euhus, D., Di Carlo, P. A. &

Khouri, N. F. Breast cancer screening. _Surg. Clin. North Am._ 95, 991–1011 (2015). Article  PubMed  Google Scholar  * National Lung Screening Trial Research Team. Reduced lung-cancer

mortality with low-dose computed tomographic screening. _N. Engl. J. Med._ 365, 395–409 (2011). * Rajput, A. & Bullard Dunn, K. Surgical management of rectal cancer. _Semin. Oncol._ 34,

241–249 (2007). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Pharmaceutical Research and Manufacturers of America. _Medicines in

development: Cancer_ [online], (2014). * 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). Article  CAS  PubMed  Google Scholar  * Pharmaceutical Research and Manufacturers of America. _Researching Cancer Medicines: Setbacks and Stepping Stones_

[online], (2014). * DiMasi, J. A. & Grabowski, H. G. Economics of new oncology drug development. _J. Clin. Oncol._ 25, 209–216 (2007). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Dowlati, A. _ et al_.

Multi-institutional phase I trials of anticancer agents. _J. Clin. Oncol._ 26, 1926–1931 (2008). Article  PubMed  Google Scholar  * 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). Article  PubMed 

Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Adamina, M. & Joerger, M. Dose-toxicity models in

oncology. _Expert Opin. Drug Metab. Toxicol._ 7, 201–211 (2011). Article  PubMed  Google Scholar  * Simon, R. _ et al_. Accelerated titration designs for phase I clinical trials in oncology.

_J. Natl Cancer Inst._ 89, 1138–1147 (1997). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Dancey, J., Freidlin, B. & Rubinstein, L. in _Statistical

methods for dose-finding experiments_ (ed. Chevret, S.) 91 (Wiley Press, 2006). Book  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  *

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). Article  CAS  PubMed 

Google Scholar  * Iasonos, A., Zohar, S. & O'Quigley, J. Incorporating lower grade toxicity information into dose finding designs. _Clin. Trials_ 8, 370–379 (2011). Article  PubMed

  PubMed Central  Google Scholar  * Yuan, Z., Chappell, R. & Bailey, H. The continual reassessment method for multiple toxicity grades: a Bayesian quasi-likelihood approach. _Biometrics_

63, 173–179 (2007). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article 

CAS  PubMed  Google Scholar  * O'Quigley, J. & Shen, L. Z. Continual reassessment method: a likelihood approach. _Biometrics_ 52, 673–684 (1996). Article  CAS  PubMed  Google

Scholar  * Cheung, Y. K. & Chappell, R. Sequential designs for phase I clinical trials with late-onset toxicities. _Biometrics_ 56, 1177–1182 (2000). Article  CAS  PubMed  Google Scholar

  * O'Quigley, J. & Conaway, M. Extended model-based designs for more complex dose-finding studies. _Stat. Med._ 30, 2062–2069 (2011). Article  PubMed  PubMed Central  Google

Scholar  * Zhang, W., Sargent, D. J. & Mandrekar, S. An adaptive dose-finding design incorporating both toxicity and efficacy. _Stat. Med._ 25, 2365–2383 (2006). Article  PubMed  Google

Scholar  * Thall, P. F. & Cook, J. D. Dose-finding based on efficacy-toxicity trade-offs. _Biometrics_ 60, 684–693 (2004). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google

Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Rogatko,

A. _ et al_. Translation of innovative designs into phase I trials. _J. Clin. Oncol._ 25, 4982–4986 (2007). Article  PubMed  Google Scholar  * Wood, L. D. _ et al_. The genomic landscapes of

human breast and colorectal cancers. _Science_ 318, 1108–1113 (2007). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Gerdes, M. J. _ et al_. Emerging understanding of

multiscale tumor heterogeneity. _Front. Oncol._ 4, 366 (2014). Article  PubMed  PubMed Central  Google Scholar  * Ludwig, J. A. & Weinstein, J. N. Biomarkers in cancer staging, prognosis

and treatment selection. _Nat. Rev. Cancer_ 5, 845–856 (2005). Article  CAS  PubMed  Google Scholar  * Henry, N. L. & Hayes, D. F. Cancer biomarkers. _Mol. Oncol._ 6, 140–146 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hollebecque, A. _ et al_. Modifying phase I

methodology to facilitate enrolment of molecularly selected patients. _Eur. J. Cancer_ 49, 1515–1520 (2013). Article  PubMed  Google Scholar  * Kwak, E. L. _ et al_. Anaplastic lymphoma

kinase inhibition in non-small-cell lung cancer. _N. Engl. J. Med._ 363, 1693–1703 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shaw, A. T. _ et al_. Ceritinib in

_ALK_-rearranged non-small-cell lung cancer. _N. Engl. J. Med._ 370, 1189–1197 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed 

Google Scholar  * Flaherty, K. T. _ et al_. Inhibition of mutated, activated BRAF in metastatic melanoma. _N. Engl. J. Med._ 363, 809–819 (2010). Article  CAS  PubMed  PubMed Central  Google

Scholar  * 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).

Article  CAS  PubMed  Google Scholar  * [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). * 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). Article  PubMed  PubMed Central  Google Scholar  * Wagner, J. A. Strategic approach to

fit-for-purpose biomarkers in drug development. _Annu. Rev. Pharmacol. Toxicol._ 48, 631–651 (2008). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar 

* Rodon, J. _ et al_. Molecular prescreening to select patient population in early clinical trials. _Nat. Rev. Clin. Oncol._ 9, 359–366 (2012). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  Google Scholar  * 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). Article  PubMed  Google Scholar  * Garon, E. B. _ et al_.

Pembrolizumab for the treatment of non-small-cell lung cancer. _N. Engl. J. Med._ 372, 2018–2028 (2015). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Robert, C. _ et al_. Nivolumab in

previously untreated melanoma without _BRAF_ mutation. _N. Engl. J. Med._ 372, 320–330 (2015). Article  CAS  PubMed  Google Scholar  * 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). Article

  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google

Scholar  * 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). Article  CAS  PubMed

  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Dy, G. K. & Adjei, A. A. Understanding,

recognizing, and managing toxicities of targeted anticancer therapies. _CA Cancer J. Clin._ 63, 249–279 (2013). Article  PubMed  Google Scholar  * de Castro, G. Jr & Awada, A. Side

effects of anti-cancer molecular-targeted therapies (not monoclonal antibodies). _Curr. Opin. Oncol._ 18, 307–315 (2006). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar

  * 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). Article  CAS

  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Grothey, A. Recognizing and managing toxicities of molecular targeted therapies for colorectal

cancer. _Oncology (Williston Park)_ 20, 21–28 (2006). Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  Google Scholar  *

Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. _J. Clin. Oncol._ 32, 579–586 (2014). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed 

PubMed Central  Google Scholar  * 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). Article  CAS  PubMed

  Google Scholar  * 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). Article  CAS

  PubMed  Google Scholar  * Josephs, D., Spicer, J. & O'Doherty, M. Molecular imaging in clinical trials. _Target Oncol._ 4, 151–168 (2009). Article  PubMed  Google Scholar  *

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). Article  CAS  PubMed 

Google Scholar  * Meric-Bernstam, F. & Mills, G. B. Overcoming implementation challenges of personalized cancer therapy. _Nat. Rev. Clin. Oncol._ 9, 542–548 (2012). Article  CAS  PubMed

  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Weiss, G. J. _ et al_. A pilot study using next-generation

sequencing in advanced cancers: feasibility and challenges. _PLoS ONE_ 8, e76438 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Tuxen, I. V. _ et al_. Personalized oncology: genomic screening in phase 1. _APMIS_ 122,

723–733 (2014). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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 2 trial. _Lancet Oncol._

http://dx.doi.org/10.1016/S1470-2045(15)00188-6. * Schwaederle, M. _ et al_. Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. _Oncologist_ 19,

631–636 (2014). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Crockford, A., Jamal-Hanjani, M., Hicks, J. & Swanton, C. Implications of intratumour

heterogeneity for treatment stratification. _J. Pathol._ 232, 264–273 (2014). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * McNeil, C. NCI-MATCH launch highlights new trial

design in precision-medicine era. _J. Natl Cancer Inst._ 107, djv193 (2015). Article  PubMed  Google Scholar  * National Cancer Institute. _NCI-Molecular Analysis for Therapy Choice

(NCI-MATCH) Trial_ [online], (2015). * Roychowdhury, S. _ et al_. Personalized oncology through integrative high-throughput sequencing: a pilot study. _Sci. Transl. Med._ 3, 111ra121 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar

  * Jia, J. _ et al_. Mechanisms of drug combinations: interaction and network perspectives. _Nat. Rev. Drug Discov._ 8, 111–128 (2009). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar

  * 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). Article  PubMed  PubMed Central  Google Scholar  * US National Library of Medicine. _ClinicalTrials.gov_ [online], (2015). * US National Library of Medicine.

_ClinicalTrials.gov_ [online], (2015). * US National Library of Medicine. _ClinicalTrials.gov_ [online], (2015). * US National Library of Medicine. _ClinicalTrials.gov_ [online], (2015). *

Cha, E., Wallin, J. & Kowanetz, M. PD-L1 inhibition with MPDL3280A for solid tumors. _Semin. Oncol._ 42, 484–487 (2015). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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).

Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Mandrekar, S. J. Dose-finding trial designs for combination therapies in

oncology. _J. Clin. Oncol._ 32, 65–67 (2014). Article  PubMed  Google Scholar  * Cannistra, S. A. Challenges and pitfalls of combining targeted agents in phase I studies. _J. Clin. Oncol._

26, 3665–3667 (2008). Article  CAS  PubMed  Google Scholar  * Dancey, J. E. & Chen, H. X. Strategies for optimizing combinations of molecularly targeted anticancer agents. _Nat. Rev.

Drug Discov._ 5, 649–659 (2006). Article  CAS  PubMed  Google Scholar  * Kummar, S. _ et al_. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent

requirements. _Nat. Rev. Drug Discov._ 9, 843–856 (2010). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  *

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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  PubMed

  Google Scholar  * US Food and Drug Administration. _Food and Drug Administration, Regulatory Information, Food and Drug Administration Safety and Innovation Act (FDASIA)_ [online], (2015).

* 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). Article  CAS  PubMed  PubMed Central 

Google Scholar  * US Food and Drug Administration. _Guidance for Industry Expedited Programs for Serious Conditions — Drugs and Biologics_ [online], (2014). * 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). Article  CAS  PubMed  Google Scholar

  * US Food and Drug Administration. _Breakthrough Therapy Approvals_ [online], (2015). * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Division of Medical Oncology/Department of Medicine, Developmental Therapeutics Program, University of Colorado Cancer Center, School of Medicine, University of Colorado Anschutz Medical

Campus, Aurora, 80045, Colorado, USA Kit Man Wong, Anna Capasso & S. Gail Eckhardt Authors * Kit Man Wong View author publications You can also search for this author inPubMed Google

Scholar * Anna Capasso View author publications You can also search for this author inPubMed Google Scholar * S. Gail Eckhardt View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS K.M.W. performed the literature search, planned the sections of the review, and wrote the entire manuscript and subsequent revisions, A.C. reviewed the

manuscript before submission. S.G.E. contributed to the contents of the manuscript and reviewed the manuscript before submission. CORRESPONDING AUTHOR Correspondence to S. Gail Eckhardt.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR

TABLE 2 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wong, K., Capasso, A. & Eckhardt, S. The changing landscape of phase I trials in oncology.

_Nat Rev Clin Oncol_ 13, 106–117 (2016). https://doi.org/10.1038/nrclinonc.2015.194 Download citation * Published: 10 November 2015 * Issue Date: February 2016 * DOI:

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