Phase I–II trial designs: how early should efficacy guide the dose recommendation process?
Authors: X. Paoletti, S. Postel-Vinay
Journal: Annals of Oncology (2018)

Oncology has the highest number of drug development failures, which calls for improvement in drug development methodology [1.Shih H.P. Zhang X. Aronov A.M. Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications.Nat Rev Drug Discov. 2018; 17: 78Crossref PubMed Scopus (6) Google Scholar]. Following the two therapeutic revolutions of targeted agents and immune therapies, several drug development paradigms have been challenged, including the systematic recommendation of the maximum tolerable dose as recommended phase II dose (RP2D) [2.Postel-Vinay S. Soria J.C. Phase I trials in oncology: a new era has started.Ann Oncol. 2015; 26: 7-9Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. More and more trials seek to determine the 'optimal biological dose' (dose associated with the most desirable effect on a pre-specified biomarker). Furthermore, although determination of safety profile of a new agent remains the primary end point of phase I trials, efficacy is more and more often brought forward as a co-primary end point. This has resulted in significant transformations over the last few years, with phase I samples sizes and number of expansion cohorts being multiplied [3.Dahlberg S.E. Shapiro G.I. Clark J.W. Johnson B.E. Evaluation of statistical designs in phase I expansion cohorts: the Dana-Farber/Harvard Cancer Center experience.J Natl Cancer Inst. 2014; 106Crossref PubMed Scopus (43) Google Scholar]. Such expansion cohorts are sometimes disguised single arm phase II studies, resulting in a two-step design made of a dose-escalation phase, based on toxicity only, followed by a 'signal-searching' expansion phase with stopping rules for futility [4.Iasonos A. O'Quigley J. Design considerations for dose-expansion cohorts in phase I trials.J Clin Oncol. 2013; 31: 4014-4021Crossref PubMed Scopus (41) Google Scholar]. In this context, should we take into account efficacy to guide dose-escalation and dose-recommendation? In this issue of Annals of Oncology, Yan et al. [5.Yan F. Thall P.F. Lu K.H. et al.Phase I–II clinical trial design: a state-of-the-art paradigm for dose finding.Ann Oncol. 2018; 29: 694-699Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar] illustrate, using clear examples, that responses at doses other than the RP2D are not integrated in the overall efficacy evaluation, and propose the phase I–II EffTox model-based design, which utilizes both toxicity and efficacy data to guide dose-recommendation. Doses are escalated if the agent is safe and if more activity is expected; doses are de-escalated if lower doses appear almost equally active but less toxic; agents without sufficient activity at any safe dose are halted early. Dose that allows reaching the optimal efficacy-toxicity trade-off is further selected. Agents such as nivolumab or pembrolizumab might have benefited from such design, as similar efficacy was observed at several dose levels in initial dose-escalation trials, and optimal dose had to be secondarily refined in later-stage randomized trials [6.Robert C. Ribas A. Wolchok J.D. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384: 1109-1117Abstract Full Text Full Text PDF PubMed Scopus (1432) Google Scholar]. However, EffTox has been reported in four trials only since its introduction in 2004 [7.Thall P.F. Cook J.D. Dose-finding based on efficacy-toxicity trade-offs.Biometrics. 2004; 60: 684-693Crossref PubMed Scopus (323) Google Scholar, 8.Shah N. Thall P.F. Fox P.S. et al.Phase I/II trial of lenalidomide and high-dose melphalan with autologous stem cell transplantation for relapsed myeloma.Leukemia. 2015; 29: 1945-1948Crossref PubMed Scopus (11) Google Scholar, 9.Brock K. Billingham L. Copland M. et al.Implementing the EffTox dose-finding design in the Matchpoint trial.BMC Med Res Methodol. 2017; 17: 112.Crossref PubMed Scopus (17) Google Scholar, 10.Whelan H.T. Cook J.D. Amlie-Lefond C.M. et al.Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.Stroke. 2008; 39: 2627-2636Crossref PubMed Scopus (18) Google Scholar, 11.Konopleva M. Thall P.F. Yi C.A. et al.Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.Haematologica. 2015; 100: 927-934Crossref PubMed Scopus (65) Google Scholar]. It is therefore important to identify settings in which this method brings significant added value, as well as to acknowledge potential limitations in its implementation. EffTox requires a homogeneous patient population selected for drug sensitivity. The four trials discussed by Yuan and colleagues were all carried out in very well-defined populations. Strict selection of patients in phase I has pros and cons. For a highly-specific drug whose mechanism of action is precisely characterized, strict selection should be recommended, whatever the frequency of the molecular profile of interest. Successful examples include the ALK-ROS inhibitor lorlatinib [12.Shaw A.T. Felip E. Bauer T.M. et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.Lancet Oncol. 2017; 18: 1590-1599Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar] and the NTRK/ROS1/ALK inhibitor entrectinib [13.Drilon A. Siena S. Ou S.I. et al.Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).Cancer Discov. 2017; 7: 400-409Crossref PubMed Scopus (545) Google Scholar]. In other situations, no selection should be applied as efficacy signals might otherwise be missed—as illustrated by the famous case of the multikinase inhibitor sorafenib, which turned out to be a poor Raf inhibitor but a potent antiangiogenic. The identification of the target population is a delicate process; for example, crizotinib appeared ineffective after the inclusion of the first unselected dose escalation cohort [14.Kwak E.L.1. Bang Y.J. Camidge D.R. et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar]; the unique observed response could luckily be associated with ALK translocation, leading to a subsequent molecular enrichment during the expansion cohort. It would have been erroneously abandoned, had an early stopping rule for activity been applied. Therefore, it may be wise to only apply enrichment in the dose-expansion phase, unless preclinical data justify it. In this respect, EffTox might be best-suited for trials with accurately defined populations. Even if the population of interest is somehow determined, can we characterize the dose–activity relationship in phase I–II trials that enroll often limited sample sizes of refractory patients? Gupta et al. (JNCI 2012) found that 95% of the phase I trials (n = 1908 patients) reported less than two objective responses, making it impossible to assess statistically any dose trends. In the absence of randomization, detecting moderate differences in activity is challenging [15.Saad E.D. Paoletti X. Burzykowski T. Buyse M. Precision medicine needs randomized clinical trials.Nat Rev Clin Oncol. 2017; 14: 317-323Crossref PubMed Scopus (49) Google Scholar]. Phase I trials should also be designed with a view to expediting drug development, which mandates rapid dose-escalation in the absence of safety concerns. Three trials using EffTox evaluated efficacy 42–90 days after treatment initiation [8.Shah N. Thall P.F. Fox P.S. et al.Phase I/II trial of lenalidomide and high-dose melphalan with autologous stem cell transplantation for relapsed myeloma.Leukemia. 2015; 29: 1945-1948Crossref PubMed Scopus (11) Google Scholar, 9.Brock K. Billingham L. Copland M. et al.Implementing the EffTox dose-finding design in the Matchpoint trial.BMC Med Res Methodol. 2017; 17: 112.Crossref PubMed Scopus (17) Google Scholar, 11.Konopleva M. Thall P.F. Yi C.A. et al.Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.Haematologica. 2015; 100: 927-934Crossref PubMed Scopus (65) Google Scholar]; waiting such delay for deciding on dose-escalation raises practical concerns. Conversely, the efficacy end point of the last trial [10.Whelan H.T. Cook J.D. Amlie-Lefond C.M. et al.Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.Stroke. 2008; 39: 2627-2636Crossref PubMed Scopus (18) Google Scholar] was defined at 48 h after treatment initiation, making EffTox very efficient. However, late toxicities [16.Postel-Vinay S. Gomez-Roca C. Molife L.R. et al.Phase I trials of molecularly targeted agents: should we pay more attention to late toxicities?.JCO. 2011; 29: 1728-1735Crossref PubMed Scopus (104) Google Scholar, 17.Postel-Vinay S. Collette L. Paoletti X. 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. 2014; 50: 2040-2049Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar] might not be well-captured by EffTox. To address this, the Late-Onset EffTox method has been proposed [18.Jin I.H. Liu S. Thall P.F. Yuan Y. Using data augmentation to facilitate conduct of phase I–II clinical trials with delayed outcomes.J Am Stat Assoc. 2014; 109: 525-536Crossref PubMed Scopus (63) Google Scholar], which incorporates time-to-event data of 'treated yet-non-assessed patients'; clinical evaluation of this method is warranted. Overall, EffTox might be most relevant when unique, homogeneous and validated early surrogate biomarkers of efficacy are available, e.g. a decrease of 2-hydroxyglutyrate under isocitrate-dehydrogenase (IDH) inhibitors in IDH-mutant acute myeloid leukemia [19.Wang F. Travins J. DeLaBarre B. et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.Science. 2013; 340: 622-626Crossref PubMed Scopus (629) Google Scholar]. Beyond efficacy data, pharmacokinetic (PK) also guide the RP2D determination. It would be interesting to retrospectively assess EffTox's performance in phase I clinical trials evaluating drugs that showed efficacy at several dose levels, and for some of which dose-escalation was halted based on PK data, e.g. nivolumab [20.Topalian S.L. Hodi F.S. Brahmer J.R. et al.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366: 2443-2454Crossref PubMed Scopus (9270) Google Scholar] or olaparib [21.Fong P.C. Boss D.S. Yap T.A. et al.Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N Engl J Med. 2009; 361: 123-134Crossref PubMed Scopus (2944) Google Scholar]. If several doses eventually proved to have similar efficacy for the former, the highest dose ultimately provided the best efficacy for the latter [22.Tutt A. Robson M. Garber J.E. et al.Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.Lancet. 2010; 376: 235-244Abstract Full Text Full Text PDF PubMed Scopus (1482) Google Scholar]. In such cases, dose-finding trials may identify a range of dose levels that present the desired PK/PD/efficacy characteristics and that may be further evaluated in randomized phase II or III dose-ranging trials. To conclude, in these exciting times where oncology drug development faces an exponential growth and leads to multiple breakthrough drug designations, the approach described by Yuan et al. is an efficient statistical tools for phase I–II trials with known populations of interest. However, because of patient heterogeneity and limited sample size, the evaluation of the best trade-off between toxicity and activity at two or three doses is best achieved in later phase randomized trials or dedicated expansion cohorts. A stimulating framework for drug development, which combines modeling, randomized phase II dose-ranging trials and adaptive designs, has been proposed by colleagues outside the oncology field [23.Musuamba F.T. Manolis E. Holford N. et al.Advanced methods for dose and regimen finding during drug development: summary of the EMA/EFPIA Workshop on dose finding (London 4–5 December 2014).CPT Pharmacometrics Syst Pharmacol. 2017; 6: 418-429Crossref PubMed Scopus (45) Google Scholar]. Cancer drug development may benefit from such approaches. None declared.