Phase I trial of sargramostim in pediatric Crohn's disease.
BACKGROUND
Improving granulocyte function may represent an effective therapy for Crohn's disease (CD). We performed a Phase I-2 trial of sargramostim (SRG) in children with CD.


METHODS
This was multicenter, open-label study in 6-16-year-old patients with moderate to severely active CD. Patients received either 4 or 6 microg/kg SRG subcutaneously daily for 8 weeks, with and without concomitant corticosteroids (CS). The primary endpoint was identification of a safe and tolerable dose in children. The secondary endpoint was establishment of the pharmacokinetics (PK). Efficacy, a tertiary endpoint, was measured by the Pediatric CD Activity Index (PCDAI). Response was defined as a decrease from baseline of > or =12.5 points and remission as absolute PCDAI of < or =10.


RESULTS
In all, 22 patients were enrolled: 12 and 10 received 4 and 6 mg/kg, respectively; 19 completed the course. Both doses were found to be safe and well tolerated. Mild injection-site reactions occurred in 90% of patients. Three patients required dose reductions due to elevated absolute neutrophil counts. Following 4 microg/kg the mean area under the curve (AUC) was 2.64 and 2.80 ngh/mL for the 6-11- and 12-16-year-old groups, respectively. The mean half-life (t(1/2)) was 1.22 and 1.59 hours, respectively. Following 6 microg/kg, the mean AUC was 5.01 ngh/mL for the 12-16-year-old group, a 1.8-fold increase. A total of 16/18 patients (88%) achieved remission or response.


CONCLUSIONS
Sargramostim at both 4 and 6 mg/kg was well tolerated. PK analysis suggested dose proportionality unaffected by CS exposure. Remission and response data are encouraging, but further trials are needed to assess efficacy.
Kelsen
Judith R
JR
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Rosh
Joel
J
Heyman
Mel
M
Winter
Harland S
HS
Ferry
George
G
Cohen
Stanley
S
Mamula
Petar
P
Baldassano
Robert N
RN
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D011994:Recombinant Proteins; D012074:Remission Induction; D014018:Tissue Distribution; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007155:Immunologic Factors; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor