The Challenge of Choosing Appropriate End Points in Single-Arm Phase II Studies of Rare Diseases [JCO Editorials] - opens in pdf file

".......In this era, with more agents to test in smaller, more specific
cohorts of patients, we can no longer afford minimally active drugs to
pass phase II studies and to enter phase III trials. In addition to
potentially exposing patients to unnecessary adverse effects from an
inactive compound, these studies may inhibit the evaluation of other
regimens in that particular group of patients. It is hoped that novel
means to measure antitumor activity at an early time point in phase II
studies may accelerate drug development. For example, a decline in
numbers of circulating tumor cells just 3 to 6 weeks after initiation of
treatment is strongly associated with overall survival in several epithelial
malignancies,11 but whether such new tools will offer significant
advantages compared with response rate and stabilization of disease
remains to be determined. A high response rate and durable disease
stabilization are probably pivotal determinants for improved quality
of life and/or prolonged overall survival and, ultimately, that is what
we want from novel regimens.
Furthermore, it is time to be more ambitious. Before starting
clinical trials, we should intensify our efforts to reveal the mechanisms
of action of the agents that we want to study, which will allow more
precise identification of the target population. We should determine
whether these preclinical targets are truly modulated, and in early
clinical trials we should aim for clinically meaningful response rates
and particularly long progression-free periods, determined by international consensus per tumor entity. Eventually, this will result in a
higher success rate of phase III studies, smaller number of patients
needed in these studies to show clinically relevant differences, and
most importantly, more rapid availability of active new drugs for
our patients."