Ensuring Success in Early Phase Oncology Clinical Trials | Page 3

Evolution in Trial Design
The goal of Phase 1 studies is to find the optimal dose of therapy, meaning one
that is high enough to be effective but not so high as to cause intolerability.
Historically, Phase 1 trial designs involved conservative methods of finding
maximum tolerated doses. Doses were started at 0. 1 mouse-equivalents, which
means 10% of dose that 10% of mice would die from. “Slow-as-you-go” 3 + 3
designs were common. Each dose level would have 3 patients. If patients at one
dose level had no dose-limiting toxicity, the next cohort was initiated at a higher
dose level. If a cohort met predefined criteria for a dose-limiting toxicity, 3 more
patients would be added to the cohort to determine if the event was an outlier
or represented a trend. If a drug continued to Phase 2, it would be at the dose
level 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 patients
are treated with doses too low to be effective (Eisenhauer et al, 2000). This
means diseased and sometimes terminally ill patients would be treated with a
drug unlikely to be effective. This can be unsettling to the physicians treating
patients, and it has raised concern among ethicists. As more targeted therapies
are being developed, the focus of Phase 1 trials is shifting toward finding
whether a drug is reaching its target tissue or is the optimal biologically active
dose. For example, the right dose of a biological like a monoclonal antibody is
not necessarily the maximally tolerated dose of this monoclonal but the dose
with 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 clear
scientific profile from preclinical data is crucial to design an adequate first trial.
Preclinical models include tumor models, transgenic models, tissue data, and
cell investigations. The goal is to know how a drug is acting: what are the
primary targets and what may be secondary targets that could become safety
concerns or produce inadvertent effects.

Develop a solid trial design. In a Phase 1 study, the primary endpoint will be
safety. Secondary endpoints might include measures to evaluate effectiveness
or narrow an indication or target population.