Phase 0 Clinical Studies in Oncology

Abstract

In the design of first-in-human (FIH) studies in oncology, some changes are incremental; others are major shifts in goals and approaches. The contemporary emphasis on molecularly targeted agents has accelerated the trend toward biomarker studies, but these investigations remain as secondary findings in phase I behind the classic end points of toxicity and occasional tumor shrinkage. In contrast, evaluation of target modulation is the primary goal of phase 0 and is intended to inform decision making regarding further development of the relevant compound. Moving PharMacodynaMics FroM a correlative to a Pivotal PositionThere is always some blurring of the stages of a compound's journey toward the clinic. For many investigators, the firstin-human (FIH) experience is viewed as the end of discovery and the beginning of development. Phase 0 studies are explicitly designed to extend the process of discovery into FIH studies to obtain information that will shape the beginning of the development process that will follow if the FIH results are satisfactory. 1,2 As indicated in Table 1, the term "phase 0" was chosen to signify a major change in the structure of FIH studies of anticancer drugs. Prior to the 1980s, FIH studies in oncology focused on determination of toxicity, with only occasional pharmacokinetic (PK) or pharmacodynamic (PD) investigations. PK studies became more common in the 1980s, eventually leading to exploration of PK-guided dose-escalation designs. 3 The 1990s brought more extensive PK and PD studies. Attempts to associate PK/PD with clinical outcomes were designated as "correlative" studies, although many were ancillary to the main development path.Phase 0 studies were introduced in the current decade and are more than mere extensions of the trend toward more biomarker studies in phase I. The fundamental difference as regards phase 0 is that PD or biomarker studies are the primary outcome, not simply correlative or ancillary. Indeed, correlations with clinical outcome are not feasible, because neither toxicity nor activity is expected in phase 0.The most important change in drug development in oncology over the past decade has been the type of compound entering the clinic. For a compound in the "molecularly targeted" category, there is often excellent preclinical data to formulate a hypothesis regarding its mechanism of action. The most relevant test of the hypothesis would be an examination of the compound's behavior in patients. It therefore seems reasonable to expect early human studies to be specifically designed to test mechanistic hypotheses. Further, the early testing of hypotheses should shape development decisions.The key to decision making is the identification of the pivotal information for a "stop-or-go" decision. The design of the first clinical study must be customized to obtain that information. Because each compound and each target is different, the most important information sought from each trial will vary. For most target-oriented programs, PD measurements are the most important. If th...

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“…The next stages in this program entail development of biomarkers of drug action to enable proof of mechanism studies in man, an approach already taken in oncology in so-called “Phase 0” clinical studies [62]. We believe this represents a rational and expeditious approach to bring to the clinic new therapeutic approaches for ALS and potentially for other CNS disorders associated with oxidative stress.…”

Experimental Therapeutic Trial Design for Pediatric Brain Tumors

“…74 In addition, phase 0 trials introduce a new ethical dilemma, particularly in pediatric patients, since these trials are more likely to require invasive procedures such as frequent blood draws or multiple tumor biopsies to determine the pharmacokinetic and pharmacodynamic of the agent being tested, while offering no direct therapeutic benefit to the patient. 75 Although phase 0 trials performed in adults can be used to develop pediatric clinical trials, in situations where the targets or cancer are pediatric-specific, the risks of phase 0 trials can outweigh the benefits.…”

Advances in Cancer Therapeutics

“…As discussed by Collins, 11 molecularly targeted therapy has accelerated a trend toward the incorporation of major shifts in goals and approaches to first‐in‐human studies in oncology. Indeed, many early studies in humans are now specifically designed to test mechanistic hypotheses that can drive important development decisions.…”