Development of immunotherapeutic strategies for early phase clinical trials

Immunotherapy has revolutionized cancer therapy and outcomes over the past 5 years. Following the initial successes of anti-PD-(L)1 and anti-CTLA-4 agents, a huge wave of novel agents and novel combinations has entered early phase trials, leading to an unprecedented exponential increase in phase 1 trials. These agents, which display different characteristics from conventional cytotoxic therapy and targeted therapies, have deeply challenged many paradigms of traditional phase 1 studies, including dose-determination, safety, pharmacokinetics and pharmacody-namics, efficacy evaluation, patient selection, routes of administration, trial design and endpoints. The historical "safety" phase 1 trials have been transformed to "phase 1 registration" trials, using seamless designs, enrolling several hundreds of patients and sometimes leading to drug approval. However, severe unexpected toxicities have also been observed, especially in combination trials, calling for cautious, rationale and measured drug development. In this chapter, we present the different types of immunotherapy agents currently being evaluated in phase 1 trials, detail the major transformations in phase 1 trial designs, and discuss challenges that will need to be tackled to rationally optimize immunotherapy development.