One of the most difficult challenges in clinical gene therapy is planning how to monitor the presence and effects of the delivered therapeutic gene in vivo. The end points selected for our phase I trial were the maximum tolerated dose (MTD) and the maximum biologically active dose (MBAD) of the E1A plasmid. Because no toxicity had been detected during the preclinical toxicity study, we initially thought that we might not reach the MTD, and thus the dose of E1A plasmid was escalated in 100% increments rather than by the Fibonacci method. MBAD, the primary end point of the study, was defined as the dose of E1A plasmid (in mg/m2) that would produce at least a 25% downregulation in HER2 expression in the tumor—the best-established end point at the time the trial was designed.
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