Risks and Benefits Associated With Novel Phase 1 Oncology Trial Designs. BACKGROUND. Although aggressive dose escalation strategies were designed to

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1 1115 Risks and Benefits Associated With Novel Phase 1 Oncology Trial Designs Shlomo A. Koyfman, MD 1 Manish Agrawal, MD 2 Elizabeth Garrett-Mayer, PhD 3,4 Benjamin Krohmal, BA 2 Elizabeth Wolf, BA 5 Ezekiel J. Emanuel, MD, PhD 2 Cary P. Gross, MD 5 1 Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio. 2 Department of Clinical Bioethics, Warren G. Magnuson Clinical Center and National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 3 Department of Oncology, Johns Hopkins University, Baltimore, Maryland. 4 Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland. 5 Department of General Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Drs. Krohmal, Emanuel, and Agrawal were supported by funding from the Department of Clinical Bioethics of the National Institutes of Health. Dr. Gross s efforts were supported by a Cancer Prevention, Control and Population Sciences Career Development Award (1K07CA-90402) and the Claude D. Pepper Older Americans Independence Center at Yale (P30AG21342). Address for reprints: Cary P. Gross, MD, Primary Care Center, Yale University School of Medicine, 333 Cedar Street, Box , New Haven, CT ; Fax: (203) ; cary. gross@yale.edu Received December 1, 2006; revision received April 26, 2007; accepted May 2, *This article is a U.S. Government work and, as such, is in the public domain in the United States of America. BACKGROUND. Although aggressive dose escalation strategies were designed to improve the risk-benefit profile of phase 1 oncology trials, they have not been adequately studied. The prevalence of several novel trial designs and their association with a variety of clinical endpoints was evaluated. METHODS. A review of the literature was performed to identify phase 1 oncology studies of cytotoxic agents published from 2002 through RESULTS. Of 955 phase 1 oncology articles initially identified, 149 studies, comprising 4532 patients, were analyzed. Only 34% of studies utilized aggressive dose escalation schemes, 22% permitted intrapatient dose escalation, and only 28% enrolled fewer than 3 patients to any dose level. Studies that allowed intrapatient dose escalation or used fewer than 3 patients per dose were not associated with different rates of response or toxicity, nor did they increase the number of patients who received the recommended phase 2 dose. However, aggressive dose escalations were associated with increased rates of both hematologic (17% vs 10%) and nonhematologic (17% vs 13%) toxicity with similar response rates. Only studies that used conservative dose escalation designs and those that studied U.S. Food and Drug Administration (FDA)-approved agents required fewer patients to complete a trial. Trials of FDA-approved agents were also associated with higher response rates than trials of non-fda-approved agents (10% vs 2%), without an increased risk of toxicity. CONCLUSIONS. Several novel aggressive design strategies intended to improve the risk-benefit profile of phase 1 oncology trials are not associated with improved clinical outcome, and may be harmful in certain instances. Cancer 2007;110: Published 2007 American Cancer Society.* KEYWORDS: phase 1, trial design, cancer, ethics. As first in human trials, phase 1 clinical oncology trials play a vital role in translating laboratory science into effective therapies. Traditionally, phase 1 oncology trials begin by administering a small dose of an experimental agent to a group of 3 or more patients. Subsequently, cohorts of patients receive increasing dosages, first by 100%, then 66%, 50%, 40%, and 33% based on a modified Fibonacci protocol. Classically, an individual patient may not receive increasing doses of the investigational agent even if he/ she experiences no significant toxicity. The trial ends when severe or life-threatening toxicities (DLTs) are experienced by a large fraction of patients at a given dosage level. The dose just below that which was associated with excessive DLT is defined as the maximum tolerated dose (MTD) and is generally recommended for phase 2 efficacy studies. 1 3 Although these elements can vary within conventional phase 1 trial designs, we use as our reference point the common Published 2007 American Cancer Society* DOI /cncr Published online 12 July 2007 in Wiley InterScience (

2 1116 CANCER September 1, 2007 / Volume 110 / Number 5 scenario in which all 3 of these features will be stipulated in the design of a trial. Phase 1 oncology trials have been the subject of considerable ethical debate for the past 20 years. 4 9 In addition to questioning the adequacy of informed consent, investigators have claimed that as many as 60% of patients are treated at subtherapeutic dose levels A recent study reported increased overall response rates for patients participating in phase 1 oncology trials and argued that their overall risk benefit profile had improved. 21 However, it did not examine whether this problem of undertreatment had changed. Moreover, whereas patients enrolled in phase 1 trials that tested therapies already approved by the Food and Drug Administration (FDA) had the highest response rates, response rates for single-agent trials of cytotoxic drugs remained stable at 4% and did not appear to contribute to the overall increase, leading an editorialist to emphasize the need for improved design strategies in this category of phase 1 oncology trials in particular. 22 Consequently, there has been a concerted effort to devise innovative strategies that would 1) increase the number of patients receiving phase 2 recommended doses, and 2) reduce the number of patients needed to complete a phase 1 trial. Simon et al. 23 suggested a variety of aggressive titration designs, including 1) allowing for intrapatient dose escalation (IPDE), 2) using fewer patients in earlier dosage levels, and 3) repeatedly increasing drug dose levels by 100%, and found them to be somewhat successful when applied to a stochastic computer model. Importantly, as opposed to other novel design strategies that measure biologic activity as an endpoint, these dose escalation strategies were primarily designed for trials of cytotoxic agents that still use toxicity as an endpoint Surprisingly little research has been conducted to evaluate the frequency with which the 3 aforementioned novel trial designs are being used, or to establish their associations with important clinical outcomes. 22 A 1996 study found that only a small minority of trials were utilizing novel designs. 2 Conversely, a more recent symposium of prominent phase 1 investigators suggested that almost every phase 1 study uses at least some aggressive design strategy, but provided no empiric data. 24 We hypothesized that these more aggressive novel design strategies were being used in more than half of all phase 1 oncology trials and would also be associated with 1) increased numbers of patients receiving biologically active doses, 2) fewer numbers of patients needed per trial, 3) increased overall response rates, and 4) higher toxicity rates. We then conducted a systematic review of single-agent phase 1 trials of cytotoxic drugs to evaluate the frequency with which these novel design strategies are being used and how they correlate with these endpoints. MATERIALS AND METHODS Study Selection Medline was searched to identify single-agent phase 1 oncology trials of cytotoxic agents published between 2002 and The search criteria initially included antineoplastic or chemotherapy or cytotoxic and was limited to humans and the English language. The subset was defined as cancer, the publication type was designated as clinical trial - phase 1, and the years of interest were selected. Our inclusion criteria were: 1) the study was a phase 1 cancer chemotherapy trial that conducted dose escalation, assessed safety, and did not allow the use of concurrent radiotherapy, cryotherapy, or photodynamic therapy; 2) only 1 agent was used in the study; 3) the investigational agent was cytotoxic, not immunotherapy, a signal transduction inhibitor, an angiogenesis inhibitor, gene therapy, or a vaccine; and 4) the study was accessible. Of 955 studies originally identified, 149 satisfied all of these criteria (Fig. 1). Data Abstraction Three investigators (S.A.K., B.K., E.W.) independently extracted all pertinent information using a formal abstraction instrument. This included demographics, prior therapy history, toxicity and response data, dose escalation strategy, the allowance of IPDE, minimum patients per dose, class and approval status of agent, and the number of patients who received the agent at or above the recommended phase 2 dose at least once. On a review of the abstracted data, discrepancy rates between data points was found to be <5% overall. Discrepancies were reviewed and resolved collectively by the abstractors. Dosing strategies comprised 3 distinct categories: 1) traditional, according to a modified Fibonacci protocol (ie, dose increased by 100% then 66%, 50%, etc.); 2) conservative, in which the initial dose increase was <100%; and 3) aggressive, in which at least the first 2 dose increases were by 100%. Study design was obtained from the methods section of each published trial in which the investigators disclosed their study design plan before enrolling patients. Similarly, IPDE was only recorded as allowed if the study explicitly indicated as such in the methods section.

3 Risks Benefits Phase 1 Trial Design/Koyfman et al Outcome Definitions Response data included the number of patients who experienced a complete response (CR), partial response (PR), and stable disease (SD) according to standard definitions. Whereas the majority of solid tumor trials used the Response Evaluation Criteria in Solid Tumors (RECIST) criteria to assess response, some used the World Health Organization (WHO) classification, the fundamental differences between them being the use of single linear summation of tumor volume (RECIST) versus a bilinear product approach (WHO), as well as the number of lesions in a given organ and/or in total that are measured. 28 Trials for patients with hematologic malignancies used their own standard definitions for response and progression. Toxicity data included possible or probable toxic deaths, nonhematologic toxicity, and hematologic toxicity. Deaths that were either explicitly reported as toxic deaths, or that were not expressly reported to be unrelated to the intervention, were defined as toxic deaths. All toxicity grades follow the standard definitions outlined in the Common Toxicity Criteria (version 2.0; 1999) and/or the Common Terminology Criteria for Adverse Events (vesion 3.0; 2003) as part of the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Grade 3/4 nonhematologic and grade 4 hematologic toxicity were recorded because these determine toxicity rules for dosing modification in the majority of phase 1 oncology studies. For this reason, grade 3 febrile neutropenia was included as a hematologic toxicity, yet alopecia was excluded. FIGURE 1. Study selection. *Includes studies that were not cancer-related, not phase 1 studies, or dose finding studies; those that did not assess the safety profile of the agent; those that included the use of radiotherapy, cryotherapy, or photodynamic therapy; and those for which the trial data was inaccessible or incomplete. **Includes signal transduction inhibitors, angiogenesis inhibitors, immunotherapy, and gene therapy. Statistical Analysis The unit of analysis was the study. For each study, rates of response, mortality, and toxicity were calculated based on the published data and exact confidence limits were estimated. For some rates, data were not available and therefore the rates for these studies were treated as missing at random. For grade 3 to grade 4 nonhematologic and grade 4 hematologic toxicities, some of the studies only provided information such that the minimum and maximum number of patients incurring the toxicity could be ascribed (ie, these studies reported the number of toxicity events rather than the number of patients with toxicity events). In these cases, we used a weighted approach for estimating the true number of patients who had experienced a toxicity, in which the estimated number of toxicities (t i ) is defined as: t i ¼ 0:75 3 min i þ 0:25 3 max i For example, in 1 study it could be assumed that at least 6, but no more than 10, patients had grade 4 hematologic toxicities. The imputed number of grade 4 hematologic toxicities for this study was 7 patients. This estimate is more conservative and also more appropriate than simply taking the average of the minimum and maximum. All multiple regressions were estimated using meta-analytic techniques. For estimating rates across studies, a random effects grouped logit regression model was used in which random intercepts were assumed for each study. For the multiple regression models, a random effects grouped logit model was also used, assuming common effects for covariates across studies. The model is essentially a generalized linear model from the binomial family with logit link in which studies are groups (ie, the unit of analysis is the study) and a random effect is included for each study. Both of these approaches are meta-analytic, accounting for variability across studies. Multiple regression models were not fit for CR and for mortality because the event rates were very low and the results were unstable. For multiple regression models, we considered covariates that demonstrated significance in simple regression models. Multiple regression models were explored by including main effects and pairwise interactions, and then removing insignificant effects and interactions 1 at a time. A Markov chain Monte Carlo approach was implemented for estimating parameters. Each of the coefficients in the

4 1118 CANCER September 1, 2007 / Volume 110 / Number 5 TABLE 1 Patient Characteristics No. of studies No. of patients Gender Age Prior treatment* Surgery/ transplantation None Median (range), y Chemotherapy Radiation No. evaluable for response Male Female No. evaluable for toxicity Total Total Study type Dose escalation Conservative 40% (59) 35% (1546) 35% (1472) 35% (1348) 58% (860) 42% (621) 54 (2 90) 65% (1004) 20% (315) 19% (296) 2% (36) Traditional 26% (37) 27% (1180) 26% (1111) 28% (1093) 60% (679) 40% (447) 56 (2 89) 74% (878) 29% (346) 17% (200) 3% (37) Aggressive 34% (49) 37% (1648) 38% (1610) 37% (1449) 55% (890) 45% (734) 53 (0.9 89) 67% (1111) 26% (434) 11% (189) 2% (32) Intrapatient dose escalation Allowed 22% (32) 22% (972) 22% (904) 21% (813) 53% (518) 47% (454) 57 (3.3 90) 73% (711) 31% (299) 15% (144) 3% (32) Not allowed 88% (112) 78% (3402) 78% (3294) 79% (3060) 58% (1897) 42% (1362) 57 (3 90) 66% (2234) 23% (780) 18% (601) 2% (73) Minimum patients per dose <3 28% (40) 30% (1269) 30% (1226) 30% (1154) 56% (706) 44% (563) 58 (3 89) 70% (886) 23% (298) 5% (60) 2% (30) 3 72% (105) 70% (3029) 70% (2929) 70% (2678) 58% (1688) 42% (1228) 57 (0.9 90) 67% (2023) 26% (801) 22% (655) 2% (75) Approval status y FDA-approved 26% (38) 22% (959) 21% (881) 20% (801) 61% (575) 39% (369) 57.5 (0.9 90) 64% (615) 22% (208) 28% (271) 3% (32) Non-FDA-approved 74% (111) 78% (3493) 79% (3389) 80% (3148) 57% (1921) 43% (1463) 57 (2 89) 69% (2396) 27% (927) 14% (487) 2% (72) All studies 100% (149) 100% (4532) 96% (4350) 89% (4027) 57% (2610) 43% (1922) 56.5 (.9 90) 68% (3084) 25% (1135) 17% (758) 2% (105) FDA indicates U.S. Food and Drug Administration. * These numbers reflect the numbers reported, but are not fully representative due to incomplete reporting. y Approval status denotes FDA approval at the time of publication of individual trials, not at the time of publication of this article. regression model was assumed to have a Gaussian diffuse prior, and random effects were assumed to have a normal distribution with variance s 2,inwhich the hyperprior for 1/s 2 is a diffuse Gamma distribution. WinBugs within OpenBugs 2.01 was used for model estimation. For each analysis, a burn-in period of 5000 iterations was performed. Then an additional 20,000 iterations were run in which every fifth iteration was saved for inference. Multiple chains were run for each analysis and traceplots were explored to ensure convergence. No convergence problems were encountered. Point estimates were defined as the posterior mean, 95% credible intervals as the 2.5th and the 97.5th percentiles of the posterior distribution, and tail probabilities as the (2-sided) proportion of area under the posterior distribution that is more extreme than the observed data. The tail probabilities and 95% credible intervals can be interpreted similarly to P values and 95% confidence intervals. Therefore, to simplify our reporting and avoid interpretive confusion, we report P values and 95% confidence intervals. RESULTS In the 149 phase 1 studies included in the sample, 4350 patients were evaluable for toxicity and 4027 were evaluable for response (Table 1). Patients predominantly had solid tumors (90%), with 9% of studies including only hematologic or lymphatic malignancies, and 1% of studies accepting patients with either solid or liquid tumors. Non-FDA-approved agents were used in 74% of the studies, whereas 26% of the agents were approved by the FDA. Overall, 26% of the trials used traditional modified Fibonacci dose escalations, 40% used more conservative escalation schemes, and only 34% of studies utilized aggressive dose escalation schemes (Table 2). Studies testing investigational agents used a conservative dose escalation 32% of the time, whereas 65% (24 of 38 studies) of studies testing FDA-approved agents used a conservative dose escalation strategy. A minority of trials either permitted IPDE (22%), or enrolled fewer than 3 patients to any dose level (28%) (Table 2). Of the 4350 patients evaluable for toxicity, 49 (1.1%) died a toxic death. Serious or life-threatening drug-related grade 4 hematologic and grade 3/4 nonhematologic toxicities were experienced by 15% and 17% of patients, respectively (Table 2). The overall objective response rate was 3% (CR 1 PR), which increased to 25% with the inclusion of SD in the definition of response (CR 1 PR 1 SD; Table 2). In addition, 57% of patients received a dose of the study

5 Risks Benefits Phase 1 Trial Design/Koyfman et al TABLE 2 Frequency and Univariate Analysis % of patients [no. of studies] (95% CI) Study design %[No.] of studies Complete 1 partial response % of patients [no.] (95% CI) Complete 1 partial response 1 stable disease % of patients [no.] (95% CI) Grade 4 hematologic toxicity % of patients [no.] (95% CI) Grade 3/4 nonhematologic toxicity % of patients [no.] (95% CI) Patients receiving recommended phase 2 dose % of patients [no.] (95% CI) Total 100% [149] 3% [141] 25% [127] 15% [124] 17% [137] 57% [134] Dose escalation Conservative 40% [59] 6% [55] 32% [46] 17% [50] 20% [54] 71% [52] (4 9) (25 39) (13 21) (15 25) (63 77) Traditional 26% [37] 2% [35] 21% [32] 10% [30] 13% [33] 46% [35] (1 3) (15 28) (7 14) (9 18) (37 57) Aggressive 34% [49] 1% [47] 23% [45] 17% [41] 17% [45] 55% [45] (1 2) (17 29) (13 21) (13 22) (46 63) Intrapatient dose escalation Yes 22% [32] 2% [29] 24% [27] 15% [24] 16% [28] 66% [30] No 78% [112] 3% [108] 26% [97] 15% [97] 17% [103] 57% [101] Minimum no. of patients per dose for first course of therapy <3 28% [40] 2% [38] 20% [36] 16% [32] 17% [35] 65% [39] (14 26) 3 72% [105] 3% [100] 28% [90] 14% [90] 17% [98] 57% [94] (24 33) FDA-approved agent FDA-approved 26% [38] 10% [34] 40% [29] 18% [30] 19% [33] 65% [35] (6 17) (31 49) (13 23) (14 25) Not FDA-approved 74% [111] 2% [107] 22% [98] 14% [94] 16% [102] 58% [99] (1 3) (19 26) (12 16) (14 19) 95% CI indicates 95% confidence interval; FDA, U.S. Food and Drug Administration. agent that was at or above the eventual recommended phase 2 dose (Table 2). Relation Between Dose Escalation and Outcome Unadjusted Analyses Conservative escalation designs had higher objective response rates (CR 1 PR 6% vs 2%; P 5.002) and higher rates of overall clinical benefit (CR 1 PR 1 SD, 32% vs 21%; P 5.03) when compared with the traditional modified Fibonacci design (Table 2). 29 Conservative escalation strategies also resulted in the highest percentage of patients that received at least 1 dose of the investigational agent at or above the recommended phase 2 dose (71% vs 46%; P <.001) (Table 2). Trials that used these conservative dose increases were associated with significantly higher hematologic (17% vs 10%; P 5.01) and nonhematologic (20% vs 13%; P 5.03) toxicity rates (Table 2). Compared with modified Fibonnaci -based designs, aggressive dose escalation strategies were associated with an increased risk of both hematologic (17% vs 10%; P 5.01) and nonhematologic (17% vs 13%; P 5.20) toxicity (Table 2). However, there were no associated increases in their rates of response (CR 1 PR, 1% vs 2% [P 5.53]; and CR 1 PR 1 SD, 23% vs 21% [P 5.79]) (Table 2). Moreover, the percentage of patients receiving the recommended phase 2 dose (55% vs 46%; P 5.18) was statistically similar for aggressive and traditional escalation designs (Table 2). Adjusted Analyses Only objective response rate (CR 1 PR) and overall clinical benefit (CR 1 CR 1 PR) were found to be significantly associated with >1 predictor in simple regression models. Therefore, according to our a priori analytic plan, only clinical benefit and objective response were considered as outcomes in multiple regression models. For each model, FDA approval status and dose escalation strategy, and their interaction terms, were included as predictors. The results

6 1120 CANCER September 1, 2007 / Volume 110 / Number 5 FIGURE 2. Association between objective response (complete response [CR] 1 partial response [PR]) and U.S. Food and Drug Administration (FDA) approval (Appr) status and dose escalation strategy. Circles represent point estimates for objective response and horizontal lines are the 95% posterior intervals. These estimates are based on a multiple logistic regression model including approval status, dose escalation strategy, and their interactions. Unappr indicates unapproved; Conserv, conservative; Trad, traditional; Aggr, aggressive. FIGURE 3. Association between clinical benefit (complete response [CR] 1 partial response [PR] 1 stable disease [SD]) and U.S. Food and Drug Administration (FDA) approval (Appr) status, dose escalation strategy, and minimum number of patients (Min Pats) in first course of therapy. Circles represent point estimates for clinical benefit and horizontal lines are the 95% posterior intervals. These estimates are based on a multiple logistic regression model including approval status, dose escalation strategy, minimum patients per dose, and their interactions. are shown in Figures 2 and 3. In Figure 2 we can see that trials using FDA-approved agents were associated with higher objective response rates, independent of dose escalation strategy, and that conservative dose escalation was associated with higher response rates than other dosing schemes. There did not appear to be much difference between the traditional and aggressive designs, and there was no evidence of an interaction between dose escalation and approval status. Different patterns are observed for clinical benefit, as shown in Figure 3, in which a minimum number of patients per dose is also included. Trials that allowed fewer than 3 patients per dose and those that used FDA-approved agents were associated with higher rates of clinical benefit (CR 1 PR 1 SD). There appeared to be a significant interaction between minimum number of patients and both other predictors, but no interaction between dose escalation and approval status. Correlation Between Intrapatient Dose Escalation, Number of Patients Per Dose, and Outcome Unadjusted Analyses Patients enrolled in trials allowing IPDE were no more likely than patients enrolled in trials not allowing IPDE to experience a clinical response (2% vs 3%), hematologic (15% vs 15%), or nonhematologic (16% vs 17%) toxicity (P >.05 for all comparisons) (Table 2). Similarly, intrapatient dose escalation was unrelated to the percentage of patients receiving the recommended phase 2 dose (66% vs 57%) (Table 2).

7 Risks Benefits Phase 1 Trial Design/Koyfman et al Patients who participated in studies that used fewer than 3 patients in initial dosage levels had similar response rates (2% vs 3%), hematologic (16% vs 14%), and nonhematologic (17% vs 17%) toxicities, and the percentage of patients receiving the recommended phase 2 dose (65% vs 57%) as compared with patients enrolled in studies that required 3 or more patients per dose level. The single exception was an increased CR 1 PR 1 SD (28% vs 20%; P 5.03) in studies that did not allow fewer than 3 patients in any given dose level (Table 2). Adjusted Analyses Trials that allowed fewer than 3 patients per dose were associated with higher clinical response rates (Fig. 3). Because it was not associated with any outcomes in univariate analyses, IPDE was not pursued in multiple regression models. Trials with FDA-Approved Agents Unadjusted Analyses Studies that tested a drug that had already been approved by the FDA for another indication were associated with increased objective response rates (CR 1 PR, 10% vs 2% [P <.001]) and higher rates of clinical benefit (CR 1 PR 1 SD, 40% vs 22% [P <.001]) compared with investigational agents. Increased tumor response to FDA-approved drugs was not accompanied by significantly increased risks of hematologic (18% vs 14%; P 5.20) or nonhematologic (19% vs 16%; P 5.38) toxicity (Table 2). Adjusted Analyses In multiple regression analyses, FDA approval and conservative dose escalation design were found to be independently associated with an increased CR 1 PR (Fig. 2). FDA approval status was also associated with clinical benefit (CR 1 PR 1 SD), as shown in Figure 3, exhibiting a significant interaction with minimum patients per dose for the first course of therapy. That is, the relation between fewer patients per dose and clinical response was stronger in studies of FDA-approved agents than in studies of non- FDA-approved agents. Number of Patients Required Per Trials There were no significant differences in the mean number of patients required to complete those trials that used aggressive dose escalations, allowed IPDE, or required fewer than 3 patients per dose relative to trials that did not use these strategies (Table 3). On multivariate analysis, among trials of non-fdaapproved agents, conservative dose escalation was associated with significantly fewer patients needed to TABLE 3 Mean Number of Patients Needed for Completion of Phase 1 Trials (Univariate Analysis) Category of dosing strategy or agent Dose escalation Conservative 26.2 Traditional 31.9 Aggressive 33.6 Intrapatient dose escalation Allowed 30.4 Not allowed 29.9 Minimum patients per < dose in first course Approval status FDA-approved 25.2 Unapproved 32.2 FDA indicates U.S. Food and Drug Administration. Mean no. of patients needed per trial complete a trial compared with trials that used traditional (22.9 vs 31.2; P 5.01), or aggressive dose escalations (22.9 vs 31.2; P 5.005). This analysis was limited in the FDA-approved sample because of the paucity of trials that used traditional or aggressive dose escalation strategies (n 5 8 and 2, respectively) (Table 4). DISCUSSION Contrary to our hypothesis, aggressive novel dosing strategies used in phase 1 oncology trials published between 2002 and 2004 did not appear to provide any advantage in the setting of single-agent trials of cytotoxic drugs. Allowing IPDE, or using fewer patients in earlier subtherapeutic dose levels, were not associated with increased response rates, or an increased proportion of patients receiving the recommended phase 2 dose. In addition, trials employing these aggressive strategies also required, on average, the same number of patients as their more traditional alternatives. Finally, despite a lack of evidence supporting increased benefit associated with aggressive dose escalation designs, patients enrolled in these studies were more likely to experience severe or life-threatening toxicity. Aggressive dosing strategies have long been advocated as a critical means of correcting some of the ethical pitfalls of phase 1 oncology trials. 22,24 The rationale is that by having fewer patients in lower dose levels, escalating the dose more quickly, and allowing patients to increase their own dose, the number of patients receiving subtherapeutic doses could be reduced. Lending partial support to this assumption, a study that examined single-agent trials

8 1122 CANCER September 1, 2007 / Volume 110 / Number 5 TABLE 4 Mean Number of Patients Needed for Completion of Phase 1 Trials Stratified by Dose Escalation and Approval Status (Multivariate Analysis) Dose Escalation Strategy FDA-approved agents Non-FDA-approved agents Mean no. of patients needed per trial Mean no. of patients needed per trial (95% CI) No. of Studies (95% CI) No. of Studies Conservative 22.4 ( ) 22.9 ( ) Traditional 20.3 ( ) 31.2 ( ) 8 29 Aggressive 16.8 ( ) 31.2 ( ) 2 47 FDA indicates U.S. Food and Drug Administration; 95% CI, 95% confidence interval. of both cytotoxic and biologic agents found that trials that allowed IPDE predicted an increased response rate with no added risk of toxicity. 30 Our data suggests that this is not the case for single-agent trials of novel, or FDA-approved, cytotoxic drugs. Although there appears to be no benefit to allowing IPDE, or using fewer patients per dose level, these methods do not appear to be any more harmful than standard protocols and may still confer psychologic benefits to patients enrolled. 31 When given the choice, a substantial number of patients chose to have the highest dose despite the proportionately increased risk for toxicity. 10 Patients may also be encouraged by the fact that, although older studies have reported that only 40% of patients received biologically active doses, we found that 57% of patients overall received a dose equal to, or greater than, the recommended phase 2 dose. 16 The association between aggressive titration designs and increased toxicity is more concerning and suggests that aggressively increasing the dose of a cytotoxic agent in a single-agent phase 1 oncology trial may adversely impact the risk-benefit ratios that enrolled patients face. Although more research is needed to confirm this finding, investigators should inform their patients of this observation, and give greater consideration to other methods of reducing the number of patients treated at subtherapeutic dose levels. Our results for conservative dose escalation strategies appear counterintuitive. We hypothesized that trials increasing doses more slowly would be associated with more patients being exposed to less potent forms of the drug and therefore with lower rates of response and toxicity and higher numbers of patients receiving subtherapeutic doses. Quite the contrary, these studies were associated with higher response rates, a greater percentage of patients who received the recommended phase 2 dose, and increased toxicity rates. One explanation is that investigators deliberately chose a more conservative design, perhaps associated with use of a higher starting dose, because of some prior experience with using a particular agent in routine clinical practice. This is supported by the fact that of the studies that tested agents already approved by the FDA, 65% used a conservative titration design, whereas only 32% of studies that tested novel agents used conservative titration designs. Our data also suggest that phase 1 oncology trials of FDA-approved agents may have an inherently different risk-benefit profile than trials of non- FDA-approved agents. Patients that participate in trials using FDA-approved therapies had significantly higher rates of response (10% vs 2% for CR 1 PR and 40% vs 22% for CR 1 PR 1 SD) than trials testing investigational agents, a finding that is consistent with the results of a recent meta-analysis. 21 Trials of FDA-approved agents also required fewer patients to achieve completion than studies of nonapproved agents (25 patients vs 32 patients). Importantly, these advantages did not come at the price of significantly higher rates of toxicity. Investigators using FDAapproved agents were likely able to begin at higher doses that were closer to therapeutic levels, escalate doses more conservatively, and still achieve a higher response rate. These findings highlight the importance of distinguishing between phase 1 oncology trials of FDA-approved agents versus nonapproved drugs, and should inform the way oncologists consider and present the risks and benefits of these trials to their patients. This study has several limitations. First, our sample of studies was heterogeneous with regard to the agents studied as well as cancer types. This consideration provided the impetus to limit our investigation to single-agent cytotoxic drugs to minimize the impact that sample heterogeneity would have on our results. However, in doing so, the generalizability of our results is limited and does not extend to the variety of design innovations currently being used and studied in noncytotoxics, most notably biologic agents and targeted therapies. Second, the lack of uniform reporting standards as well as publication biases may have also led to overestimated or underestimated response and toxicity rates. However, because publication of phase 1 studies is not dependent on response rates, and there was no indication of a suppression of adverse mortality data,

9 Risks Benefits Phase 1 Trial Design/Koyfman et al publication bias may be less likely than in other types of meta-analysis. The use of varying response criteria can also be a potential confounder. From a practical standpoint, our priority was to establish a large enough sample size to adequately power our analysis for our primary outcomes. We also reasoned that because differences between these response criteria are subtle and often yield clinically identical results, we would be justified including all studies without controlling for this variable. 28 We also did not distinguish between trials that merely allowed IPDE by design and those in which patients actually received increasing dose levels, mostly because of variability in reporting. Some have also questioned the utility of stable disease as an endpoint, especially in uncontrolled, phase 1 trials, in which cancers of varying biologic behaviors are studied. 32 Nevertheless, we included this additional endpoint in our analysis, relying on our robust and heterogeneous sample size, and following many recent phase 1 trials and meta-analyses that have reported significant findings in this area. 21,29 Finally, we must always be cautious about establishing causality in a retrospective analysis. Conclusions Although some novel dosing strategies appear to have little impact on clinical endpoints, others may in fact be harmful. The allowance of IPDE and the use of fewer than 3 patients in initial dosage levels do not appear to impact response or toxicity rates, the percentage of patients who receive the recommended phase 2 therapeutic dose, or decrease the average number of patients needed to complete a trial. Aggressive dose escalation designs expose patients to greater risk of toxicity with no increased likelihood of benefit. These innovations do not appear to deflect some of the most fundamental ethical challenges made against these trials, and perhaps more attention ought to be focused on alternative models aimed at improving trial design. For cytotoxic agents, these may include trials that adjust dosing regimens in a dynamic fashion throughout the study period, such as the Continual Reassessment Model (CRM) and its variants, as well as efficacy toxicity trade-off models that use both toxicity and response data to optimize dosing Also, whereas our study was limited to cytotoxics, using biologic and pharmacokinetic endpoints for newer noncytotoxic agents may prove more effective in improving the risk-benefit profile of phase 1 oncology trials REFERENCES 1. Arbuck SG. Workshop on phase I study design. 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