Introduction

In 2000, Lancet published results of a phase 1 study testing augmerosen in volunteers receiving the standard chemotherapy dacarbazine for melanoma. Augmerosen belongs to a class of genetic therapies – called antisense agents – that work by blocking expression of specific genes. In this case, the target was BCL-2, which prevents cells that have sustained DNA damage from undergoing “cell suicide.” The idea of the study, then, was to use augmerosen to release the genetic “brake” on cell suicide so that tumor cells would die after chemotherapy.

The study results were favorable: augmerosen combined with the chemotherapy drug dacarbazine proved safe even at the highest dose tested, with no volunteers developing life-threatening and/or unanticipated toxicities. In addition, six of the fourteen volunteers showed tumor shrinkage, and for two others, tumors stopped growing. In one figure, numerous thick, pigmented growths crowd a volunteer's forearm before the start of treatment; after, the tumors are reduced to a series of small moles. Whereas patients treated for advanced melanoma might typically live another five months, these study volunteers survived a median of twelve.

The study was valuable in the way phase 1 studies are typically valuable. According to one authoritative source, “the primary purposes of classic phase I studies are to investigate toxicity of organ systems involved, establish an optimalbiological dose, estimate pharmacokinetics, and assess tolerability and feasibility of the treatment. Secondary purposes are to assess evidence for efficacy, investigate the relation between pharmacokinetics and pharmacodynamics of the drug, and targeting.