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, comprising of 2.5 mg/kg IV once daily x 4 days, usually from day
-5 prior to transplantation leads to markedly different exposures across the
pediatric age range. Also the peripheral blood lymphocyte count at the first
dose of Thymoglobulin is a variable influencing pharmacokinetics which is
currently not taken into account. In a retrospective analysis, low post-HCT
Thymoglobulin AUC was associated with a high chance on successful IR, defined
as a CD4+ T-cell count >50 x 10e6/L in 2 consecutive measurements within 100
days. This count was chosen based on literature, where counts under this limit
are associated with a higher probability of viral reactivations. Currently, 60%
of patients reach this criterion of immune-reconstitution (HCT*s in Utrecht and
Leiden from 2004-2012, n=260), which is associated with a lower incidence of
relapse- and non-relapse mortality.
Low pre-HCT exposure on the other hand was associated with reduced GvHD and
rejection. Using the optimal exposure combined with the PK-model, we developed
an individual dosing regimen for Thymoglobulin, aiming for improved IR and a
reduction of GvHD and graft failure. The goal of this study is to investigate
the effects of an individualized PK/PD based dosing regimen for Thymoglobulin
on immune reconstitution after HCT.

To investigate whether an individualized dosing regimen for Thymoglobulin leads
to a better immune reconstitution after HCT (definition as in primary
endpoint), as compared to historically non-individualized treated patients
receiving Thymoglobulin as a fixed dose per kilogram body weight. The
individualized dosing regimen is based on a previously treated pediatric cohort
on which a population PK-PD analysis was performed. The dosing regimen was
compiled using this cohort, taking into account the influence of body weight
and pre-Thymoglobulin lymphocyte count and the observed variability.

Interventional, phase II, open label, clinical trial using historical controls

Patients 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.

The risks of this study include inadequate treatment by too low Thymoglobulin
exposure or overtreatment by a too high exposure. This can contribute to a
higher incidence of HCT-related complications such as acute and chronic GvHD
and graft failure, or delayed or absent immune reconstitution, in low and high
exposure respectively. Possible benefit of this study is better controlled
Thymoglobulin serum levels, including lower post-HCT Thymoglobulin exposure,
leading to improved immune reconstitution, and an increase in pre-HCT exposure
aimed to prevent GvHD and graft failure. If applicable, the above-mentioned
complications will be treated according to the current standardized treatment
SOPs for GvHD and viral reactivations.
This study will be conducted in pediatric patients, as there are significant
changes in pharmacokinetics in this population, which are not implemented in
current guidelines. This leads to markedly differing exposure, being associated
with treatment outcome.

The burden for patients in this study involves blood samples taken from an
existing central line (n=1-7, depending on number of doses of Thymoglobulin,
1-3 ml per sample). Follow-up and assessment of endpoints are performed
according to the standard HCT care and therefore do not impose an additional
burden.