A Phase I/II adaptive design to determine the optimal treatment regimen from a set of combination immunotherapies in high-risk melanoma.

In oncology, vaccine-based immunotherapy often investigates regimens that demonstrate minimal toxicity overall and higher doses may not correlate with greater immune response. Rather than determining the maximum tolerated dose, the goal of the study becomes locating the optimal biological dose, which is defined as a safe dose demonstrating the greatest immunogenicity, based on some predefined measure of immune response. Incorporation of adjuvants, new or optimized peptide vaccines, and combining vaccines with immune modulators may enhance immune response, with the aim of improving clinical response. Innovative dose escalation strategies are needed to establish the safety and immunogenicity of new immunologic combinations. We describe the implementation of an adaptive design for identifying the optimal treatment strategy in a multi-site, FDA-approved, phase I/II trial of a novel vaccination approach using long-peptides plus TLR agonists for resected stage IIB-IV melanoma. Operating characteristics of the design are demonstrated under various possible true scenarios via simulation studies. Overall performance indicates that the design is a practical Phase I/II adaptive method for use with combined immunotherapy agents. The simulation results demonstrate the method's ability to effectively recommend optimal regimens in a high percentage of trials with manageable sample sizes. The numerical results presented in this work include the type of simulation information that aid review boards in understanding design performance, such as average sample size and frequency of early trial termination, which we hope will augment early-phase trial design in cancer immunotherapy.