Dose-escalation cohort studies

The problem with this modification is that after the first occasion, subjects are at different dose levels on any particular study day, making it difficult to obtain data from adequate numbers of subjects before dose escalation without using large cohorts. 

The number of subjects per cohort needed for the initial study depends on several factors. If a well established pharmacodynamic measurement is to be used as an endpoint, it should be possible to calculate the number required to demonstrate significant differences from placebo by means of a power calculation based on variances in a previous study using this technique. However, analysis of the study is often limited to descriptive statistics such as mean and standard deviation, or even just recording the number of reports of a particular symptom, so that a formal power calculation is often inappropriate. There must be a balance between the minimum number on which it is reasonable to base decisions about dose escalation and the number of individuals it is reasonable to expose to a NME for the first time. To take the extremes, it is unwise to make decisions about tolerability and pharmacokinetics based on data from one or two subjects, although there are advocates of such a minimalist approach. Conversely, it is not justifiable to administer a single dose level to, say, 50 subjects at this early stage of ED. There is no simple answer to this, but in general the number lies between 6 and 20 subjects. 

These studies were multiple-dose, ascending-dose tolerance studies with three patients per cohort, except at the MTD where usually six or more patients were enrolled. In the event of a DLT, the cohort was to be expanded up to six patients. Dose escalation was to proceed until the MTD was identified, with MTD being defined as the highest dose at which less than two of six patients experienced DLT during, or as a consequence of, treatment with tasidotin. Toxicity was analyzed according to the National Cancer Institute Common Toxicity Criteria, version 2.0... 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

A Phase I single-dose-escalation study of aerosolized tgAAVCF was conducted in adult CF patients with mild lung disease (59). Three patients were enrolled in each offour-dose cohorts, receiving 10 -10 DRPoftgAAVCF in... 

---