Clinical trial designs for therapeutic cancer vaccines

Therapeutic cancer vaccines have characteristics that require a new paradigm for phase I and phase II clinical development. Effective development plans may take advantage of some of the following observations: Dose ranging safety trials are not appropriate for many cancer vaccines. Dose ranging trials to establish an optimal biologic dose are often not practical. We have presented an efficient design of Korn et al. (4) to identify an immunogenic dose. Vaccine efficacy can be efficiently evaluated with tumor response as endpoint utilizing a two stage design with only 9 patients in the first stage. If no partial or complete responses are observed in the initial 9 patients, accrual to the trial is terminated. Optimization of vaccine delivery by comparing results of single arm phase II studies using immunological response as endpoint is problematic because of assay variation and potential non-comparability of patients in different studies. Randomized screening studies can be used to efficiently optimize vaccine immunogenicity. Efficiency in use of patients depends on having assay variation and inter-patient variability small relative to the difference in immunogenicity to be detected. Phase II studies using time to progression as endpoint are most interpretable if they employ randomized designs with a no-vaccine control group. Such designs may use an inflated type 1 error rate, and need not be prohibitively large if patients with rapidly progressive disease are studied. Interim monitoring plans may effectively limit the size of the trials by terminating accrual early when results are not consistent with the targeted improvement.