Tailoring early-phase clinical trial design to address multiple research objectives

Abstract

Introduction-In contemporary oncology drug development, implementation of novel earlyphase designs with the ability to address multiple research objectives are needed to better refine regimens. This paper describes an adaptive design strategy for identifying a range of optimal regimens based on two endpoints within multiple cohorts. The proposed design was developed to address objectives in an early-phase trial of cancer vaccines in combination with agonistic antibodies to CD40 and CD27.Materials and methods-We describe a model-based design strategy that was developed for a trial evaluating the safety and immunogenicity of vaccination with i) peptides plus CD40 antibody and TLR3 ligand, ii) systemic administration of an agonistic CD27 antibody, and c) to assess immune response from i) and ii) compared to optimal controls in participants with stage IIB-IV melanoma.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities

“…Limited absorption, distribution, metabolism, and excretion (ADME) characterization due to poorly conducted dose-finding trials jeopar-dize the chance of approval of some personalized TCVs that might have otherwise provided clinical benefit to patients. [84][85][86] Figure 3 illustrates the complexity of the components impacting dosing strategy and dose response for a personalized TCV. Absorption and biodistribution of personalized TCVs are influenced by a myriad of factors, including delivery method, lymphatic uptake by mononuclear phagocytes, formulation, critical quality attributes, payload/carrier ratio, and in vivo "leakage" (premature release) of antigen-encoding material from carriers.…”

“…97 To the extent that tolerability allows, the vaccination dose should be increased until the cellular immune response plateaus. 85 Only highavidity T cells are presumed capable of being stimulated by extremely low concentrations of antigen, whereas higher concentrations have the potential to stimulate lower avidity T cells. 100 Mouse models are commonly used to inform fundamental understanding around the most effective route of administration, adjuvant, carrier, dose, and schedule, providing insight into the kinetics of antigenic stimulation to be further refined in clinical trials.…”

“…d Lack of clear dose-response relationships, due to small trial populations and disease heterogeneity, makes it difficult to use surrogate markers of immunity to identify clinical responders, and induced T cell responses in true clinical responders may be too low for statistical assessment4,113 d Clinical anti-tumor efficacy not observed despite evidence of immunological activity4,113 d Inadequate characterization of the shape of the immune response curve due to insufficient dose levels/patients tested105 d Lack of implementation of quantitative modeling approaches to provide insight on optimal dose-response relationships106,107 d Speed of development and commercial pressure leading to trial design with inadequate testing of dosing strategies and, during late-stage development dose selection, bias to favor safety over efficacy, jeopardizing future licensure[84][85][86] …”

Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment

“…With the dose increasing, the immune response is intensified and the occurrence of immune related adverse events also elevate. The key point is to find the balance between efficacy and safety (82)(83)(84)(85)(86)(87). Owing to lack of more clinical data, further studies about dose and administrating route are urgently required (64).…”