Evolution in Trial Design
The goal of Phase 1 studies is to find the optimal dose of therapy, meaning onethat is high enough to be effective but not so high as to cause intolerability.Historically, Phase 1 trial designs involved conservative methods of findingmaximum tolerated doses. Doses were started at 0. 1 mouse-equivalents, whichmeans
10% of dose that 10% of mice would die from. “Slow
go” 3 + 3
designs were common. Each dose level would have 3 patients. If patients at onedose level had no dose-limiting toxicity, the next cohort was initiated at a higherdose level. If a cohort met predefined criteria for a dose-limiting toxicity, 3 morepatients would be added to the cohort to determine if the event was an outlieror represented a trend. If a drug continued to Phase 2, it would be at the doselevel just prior to the one where a dose-limiting toxicity was seen.Having an approach that is too conservative can lead to trials in which patientsare treated with doses too low to be effective (Eisenhauer et al, 2000). Thismeans diseased and sometimes terminally ill patients would be treated with adrug unlikely to be effective. This can be unsettling to the physicians treatingpatients, and it has raised concern among ethicists. As more targeted therapiesare being developed, the focus of Phase 1 trials is shifting toward findingwhether a drug is reaching its target tissue or is the optimal biologically activedose. For example, the right dose of a biological like a monoclonal antibody isnot necessarily the maximally tolerated dose of this monoclonal but the dosewith a saturation of its target.
Keys for Setting up Phase I Oncology Studies
The major challenge in entering clinical development is translating in vitro and
preclinical data into a clinical regimen,”
according to Jurgen Frisch, MD, chief medical officer of European operations at Clinipace Worldwide. Knowing a clearscientific profile from preclinical data is crucial to design an adequate first trial.Preclinical models include tumor models, transgenic models, tissue data, andcell investigations. The goal is to know how a drug is acting: what are theprimary targets and what may be secondary targets that could become safetyconcerns or produce inadvertent effects.
Develop a solid trial design.
In a Phase 1 study, the primary endpoint will besafety. Secondary endpoints might include measures to evaluate effectivenessor narrow an indication or target population.