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Keywords: CAR-T, Clinical Trial, Estimand
Autologous chimeric antigen receptor (CAR) T cells therapies offer exciting new treatment options in many hematological malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM).
Compared to traditional treatment options such as chemo or chemo-immunotherapies, CAR T treatment is unique in several ways: 1) Eligible patients may receive bridging therapies and pre-conditioning therapies before the eventual autologous CAR T cell infusion. 2) Following the initial CAR T infusion, CAR T cells undergo expansion and maintain persistency in vivo. Such unique cellular kinetics characteristics impose new challenges to the classical PK/PD and dose-response framework. 3) Many new agents are introduced as a “bridge” to stem cell transplant (SCT), which is regarded as a potential curative option. Given the potential of CAR T treatment, it is of great interest to evaluate the effect of CAR T treatment either as a stand-alone therapy, or as part of a treatment strategy that includes subsequent consolidation (e.g. by SCT) therapy.
To address these unique challenges, target treatment effect of interest must be carefully specified in the design and analysis of CAR-T clinical trials. Methodological considerations will be discussed under the estimand framework (ICH E9 addendum).