Phase I trial improvement: a question of patient selection, trial design, or both?

The overall intent of a cancer phase I trial design is to evaluate the safety of a new drug (or drug combination), determine an optimal dose or dose range, and identify adverse effects. These trials are typically small and enroll patients with advanced cancer for which no standard treatment exists, usually because approved treatments have failed to prevent disease progression. Phase I trial design is an active research area with the goals of (1) determining a more precise estimate of the optimal drug dose or dose range, and (2) providing safe treatment of patients at doses close to the therapeutic dose. The latter is meant to minimize the number of patients treated at subtherapeutic dose levels. A less researched area is that of patient selection for phase I trials. In the article that accompanies this editorial, Hyman et al describe a patient selection tool for phase I trials designed to improve patient safety and increase the trial efficiency and scientific validity. To this end, they provide a nomogram designed to predict a patient’s risk for a serious drug-related toxicity (SDRT) at the time of enrollment so that patients at high risk for an SDRT (those with a predicted probability of experiencing an SDRT in cycle 1 30%) can be excluded in order to improve the safety and efficiency of phase I trials. Hyman et al present an excellent analysis of variables associated with the risk of a patient experiencing an SDRT during the first cycle of treatment. They then create a nomogram that can be used to predict the probability that an individual patient will experience an SDRT. The resulting nomogram likely represents the highest quality tool presently available for estimating the probability an individual will experience an SDRT given the available data. However, taking a step back and looking at the bigger picture there are several questions that can be raised: (1) are patient safety, trial efficiency and trial validity issues that need to be addressed in phase I trials as they are currently conducted? and (2) is it really patient selection or phase I trial design that is problematic? Hyman et al report that the observed SDRT rate for the 3,104 patients enrolled in Cancer Therapy Evaluation Program–sponsored phase I trials activated between the years 2000 and 2010 was 23.5% with 0.4% of patients dying of drug-related toxicity during cycle 1. Is this an unacceptable rate? This is difficult to answer because there is no established benchmark for what the rate should be. It cannot be zero because to determine a maximum-tolerated dose (MTD), there will be patients who experience SDRT. A common definition of an MTD is a dose at which less than 30% of patients experience an SDRT during the first cycle of treatment. The historical rate is 23.5%, so perhaps this is acceptable. Setting aside the question of whether the current level is acceptable, most people would agree that decreasing the SDRT would be desirable. However, it is not clear whether the proposed nomogram would accomplish this and by how much the rate would be lowered. Hyman et al do not indicate what the rate would have been for the historical cohort if they had applied their nomogram. In addition, it is not clear whether the nomogram would be useful for individual patient decision making regarding whether to enroll in a phase I trial due to safety concerns. In that regard, the nomogram’s c-index appears to be between 0.60 to 0.64, a discriminatory capability that falls quite short of levels demanded for nomograms to be useful in clinical practice. A potential unintended consequence for excluding patients deemed at high risk for an SDRT according to the nomogram is that there might be increased toxicity in subsequent phase II and phase III trials. In particular, if the drug dose is selected based on a cohort of patients that includes some at higher risk of an SDRT during cycle 1, it will likely be a conservatively safe dose for patients in future trials. Specifically, the toxicity in future trials would be at an acceptable level because the rates of SDRTs would probably be at the same or lower levels than seen in the phase I trial. However, if patients at an increased risk for an SDRT are removed from phase I trials, it may result in selecting dose levels that yield greater proportions of phase II and phase III patients experiencing an SDRT, potentially yielding unacceptably high toxicity in these trials. The chance of this occurring would be quite high if patients who would have been deemed to be at high risk for an SDRT by the nomogram were allowed to enroll on phase II and phase III trials. Changing the patient selection process to only allow fitter patients to enroll on phase I trials should be done cautiously because it is not clear what impact this may have with respect to patient safety on subsequent trials. Hyman et al also posited that the use of their nomogram improves the scientific validity of phase I trials. The authors do not provide evidence to support this claim. It is true that using the nomogram to select patients for a phase I trial would result in more homogenous groups of patients being selected for phase I trials. However, the lack of reproducibility is more likely due to small sample sizes for phase I trials and differences between patients enrolled on phase I trials and those enrolled on phase II and II trials. Phase I trials often have small sample sizes (ie, 50 patients), which increase the chance that patients who were enrolled are not representative of the general patient population. In addition, phase I patients generally have more advanced disease than phase II and III patients. Thus, such patients JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 6 FEBRUARY 2