Prospective Analysis of an individualized dosing Regimen of ATG (Thymoglobulin) in Children Undergoing HCT: redUcing Toxicity and improving Efficacy – a single arm phase II study

Thymoglobulin® was introduced to the conditioning regimen in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Side effects of Thymoglobulin® include delayed immune reconstitution (IR) of donor T-cells due to its long half-life and potential remaining circulating drug post-HCT resulting in an increased probability of viral reactivations/infections. The currently used dosing regimen for Thymoglobulin in children leads to markedly different exposures across the pediatric age range. Low post-HCT Thymoglobulin AUC is associated with a high chance on successful immune reconstitution, important for preventing viral reactivations and relapse. High pre-HCT exposure on the other hand led to a decrease in GvHD and rejection.We defined an optimal exposure based on historical data with which a PK-model was generated, and developed an individual dosing regimen for Thymoglobulin, aiming for improved IR and a reduction of GvHD and graft failure. The goal of this prospective study is to investigate the effects of an individualized PK/PD based dosing regimen for Thymoglobulin on immune reconstitution after pediatric HCT.

Our hypothesis is that individualized dosing of Thymoglobulin will result in an improved immune reconstitution, without significantly increasing the risk on aGvHD. This may lead to an improved survival, both through reducing non-relapse mortality (GvHD, viral reactivations) as well as relapse mortality. As a final step in the validation process of our proposed individualized dosing strategy, this needs to be studied in in a prospective, phase II trial.

Primary endpoints will be assessed at 100 days post-HCT, engraftment at 40 days post-HCT, other endpoints at 1 year follow up

Patient will receive an individualized dose of Thymoglobulin according to a PK/PD derived dosing regimen, as opposed to a fixed standard dose of 10 mg/kg Thymoglobulin, the current standard of care.