2578 Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.
Is the “3+3” Dose-Escalation Phase I Clinical Trial Design Suitable for Therapeutic Cancer Vaccine Development? A Recommendation for Alternative Design
