Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘The primary aims of a Phase I trial might be to:• determine how well the investigational drug can be tolerated in humans• find the maximum-tolerated dose in humansSecondary aims might be to:• study the drug’s clinical pharmacology on human patient volunteers whowere typically nonresponsive to conventional therapy• study the drug’s toxicity on human volunteersExampleAn example of a Phase I trial is illustrated by Bomgaars et al., who conducteda study to determine the maximum-tolerated dose, dose-limiting toxicities,and pharmacokinetics of intrathecal liposomal cytarabine in children withadvanced meningeal malignancies [2]. The investigators enrolled 18 patients,who were given cytarabine either through an indwelling cerebral ventricularaccess device or via lumbar puncture. The initial dose was 25 mg, but this wassubsequently escalated to 35 mg, and then to 50 mg.The authors found that headache due to arachnoiditis was dose limiting in twoof eight patients on the 50 mg dose, despite concomitant treatment withdexamethasone. They also found that eight of the 14 patients assessable forresponse demonstrated evidence of benefit (manifest as no further diseaseprogress or disease remission). Based on these results, the authors suggested thatthe maximum-tolerated and recommended optimal dose of liposomal cytarabinewas 35 mg, if given together with dexamethasone twice daily.Phase II trialsThe primary aims of a Phase II clinical trial are:• initial assessment of a drug’s therapeutic effects• initial assessment of a drug’s consequent adverse effectsPhase II trials are usually performed across multiple study centers, and might eveninclude a control group and, possibly, randomization. If treated patients show anadequate response to treatment, the drug will be further evaluated in a large-scalePhase III (randomized) clinical trial.17