The investigators hypothesize that graft rejection after hematopoietic stem cell transplant (HSCT) is primarily driven by interferon gamma, and prophylactic interferon gamma inhibition in high-risk patients will prevent graft rejection. Additionally, knowledge of emapalumab PK/PD and in vitro mechanistic effects of emapalumab in this novel setting will guide optimization of dosing regimens and treatment approaches in future studies.
Graft rejection is a devastating and understudied complication of hematopoietic stem cell transplant (HSCT) due to the lack of available interventions outside of re-transplantation. Re-transplantation is challenging and is associated with increased morbidity and mortality. The purpose of this study is to learn more about emapalumab and its ability to prevent graft rejection in hematopoietic stem cell transplant (HSCT) recipients. Specifically, the study doctors would like to learn more about the efficacy and treatment of emapalumab as a prophylactic intervention for graft rejection.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
20
Subjects will be randomized to either receive a 3mg/kg or 10mg/kg intravenous dose of emapalumab once and may receive up to two additional doses if clinical concern for impending graft rejection develops.
Subjects will be randomized to either receive a 3mg/kg or 10mg/kg intravenous dose of emapalumab once and may receive up to two additional doses if clinical concern for impending graft rejection develops.
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
RECRUITINGPreliminary efficacy of Emapalumab
Measured by the incidence of graft rejection in the treatment cohort.
Time frame: 100 days
Maximum plasma concentration (Cmax) of emapalumab after 10 mg/kg prophylactic dosing
* Measured by the Cmax (ng/mL) of emapalumab after 10mg/kg dose * Cmax values will be calculated using every 48 hour blood collections beginning at the time of emapalumab administration (day 1 after HSCT) until day 21.
Time frame: Until day 42 or time of rescue dose, whichever is sooner
Maximum plasma concentration of emapalumab after 3 mg/kg prophylactic dosing
* Measured by the Cmax (ng/mL) of emapalumab after 3 mg/kg dose * Cmax values will be calculated using every 48 hour blood collections beginning at the time of emapalumab administration (day 1 after HSCT) until day 21.
Time frame: Until day 42 or time of rescue dose, whichever is sooner
Maximum plasma concentration of emapalumab after rescue dosing
* Measured by the Cmax (ng/mL) of emapalumab after 10mg/kg rescue dose(s). * Cmax values will be calculated using every 48 hour blood collections beginning at the time of emapalumab rescue dose administration and continuing for 1 week after the rescue dose.
Time frame: Until day 42 or 1 week after rescue dose, whichever is later
Number of patients in 10 mg/kg prophylactic dosing arm who maintain CXCL9 levels below the upper limit of normal for the test (</= 647 pg/mL).
* Measured by plasma CXCL9 levels (pg/mL) * CXCL9 levels will be measured every 48 hours beginning at the time of prophylactic emapalumab administration (day 1 after HSCT) and until day 21 after HSCT. Additionally, weekly CXCL9 levels will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or 1 week after rescue dose, whichever is later
Number of patients in 3 mg/kg prophylactic dosing arm who maintain CXCL9 levels below the upper limit of normal for the test (</= 647 pg/mL).
* Measured by plasma CXCL9 levels (pg/mL) * CXCL9 levels will be measured every 48 hours beginning at the time of prophylactic emapalumab administration (day 1 after HSCT) and until day 21 after HSCT. Additionally, weekly CXCL9 levels will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or 1 week after rescue dose, whichever is later
Number of patients in 10 mg/kg prophylactic dosing arm who maintain CXCL9 levels below 2.6x the upper limit of normal for the test.
* Measured by plasma CXCL9 levels (pg/mL). This cutoff was chosen based on our prior publication which showed CXCL9 levels above this threshold were associated with graft rejection. * CXCL9 levels will be measured every 48 hours beginning at the time of prophylactic emapalumab administration (day 1 after HSCT) and until day 21 after HSCT. Additionally, weekly CXCL9 levels will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or 1 week after rescue dose, whichever is later
Number of patients in 3 mg/kg prophylactic dosing arm who maintain CXCL9 levels below 2.6x the upper limit of normal for the test.
* Measured by plasma CXCL9 levels (pg/mL). This cutoff was chosen based on our prior publication which showed CXCL9 levels above this threshold were associated with graft rejection. * CXCL9 levels will be measured every 48 hours beginning at the time of prophylactic emapalumab administration (day 1 after HSCT) and until day 21 after HSCT. Additionally, weekly CXCL9 levels will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or 1 week after rescue dose, whichever is later
Emapalumab half-life after 10 mg/kg prophylactic dosing
* Measured using the volume of distribution (L) and clearance (L/h) of emapalumab after 10mg/kg prophylactic dose * Half-life will be calculated using every 48 hour sample collections beginning at the time of emapalumab administration (day 1 after HSCT) until day 21. Additionally, weekly blood samples will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or time of rescue dose, whichever is sooner
Emapalumab half-life after 3 mg/kg prophylactic dosing
* Measured using the volume of distribution (L) and clearance (L/h) of emapalumab after 3mg/kg prophylactic dose * Half-life will be calculated using every 48 hour sample collections beginning at the time of emapalumab administration (day 1 after HSCT) until day 21. Additionally, weekly blood samples will be obtained from day 21 until day 42 after HSCT.
Time frame: Until day 42 or time of rescue dose, whichever is sooner
Emapalumab half-life after 10mg/kg rescue dosing
* Measured using the volume of distribution (L) and clearance (L/h) of emapalumab after 10mg/kg dose(s) * Half-life will be calculated using every 48 hour blood collections beginning at the time of emapalumab rescue dose administration and continuing for 1 week after the rescue dose.
Time frame: Until day 42 or time of rescue dose, whichever is sooner
Overall survival
• Measured by overall survival of patients who receive prophylactic emapalumab.
Time frame: 100 days after HSCT.
Number of patients who develop infections
Measured by the incidence of infection in patients who receive prophylactic emapalumab.
Time frame: 100 days after HSCT.
Number of patients who develop mixed chimerism.
Measured by the incidence of mixed chimerism in patients who receive prophylactic emapalumab.
Time frame: 100 days after HSCT.
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