A Phase I Trial of Monoclonal Antibody HGS-ETR2 (Lexatumumab) With or Without Interferon Gamma in Patients With Refractory Pediatric Solid Tumors
Pediatric solid tumors represent approximately one fourth of cancer diagnoses in children.
Despite intensive regimens, patients with metastatic or recurrent tumors have unsatisfactory
survival rates. Therefore new therapies are needed to improve outcomes.
Members of the TNF ligand superfamily induce death in tumor cells through direct ligation of
death receptors and apoptosis induction.
TRAIL (TNF-related apoptosis inducing ligand) has specific anti-tumor activity against a
wide range of tumor cells without inducing death in normal cells. TRAIL-induced apoptosis
has been demonstrated in a wide variety of pediatric solid tumors, including Ewing's
sarcoma, osteosarcoma, neuroblastoma, and rhabdomyosarcoma.
HGS-ETR2 (Human Genome Sciences; human monoclonal antibody) is a fully human monoclonal
antibody that agonistically binds TRAIL receptor 2 and, like TRAIL itself, induces apoptosis
in a variety of malignant cell types with little effect on normal cells.
Limited caspase 8 expression is a primary factor in limiting to TRAIL mediated cell death in
some tumors; interferon gamma has been shown to be effective in increasing caspase-8
expression in tumors and in restoring sensitivity of tumors to TRAIL mediated cell death.
To determine the tolerance of the adult maximum tolerated dose and dose limiting toxicities
of lexatumumab in patients with refractory pediatric solid tumors.
To determine the MTD of lexatumumab in the presence of fixed dosing of interferon gamma 1b
at 25 mcg/m(2) SC three times/week, which is less than the FDA approved dose.
To assess the pharmacokinetics of lexatumumab or lexatumumab in combination with interferon
gamma 1b in patients with pediatric malignant tumors refractory to standard therapy.
Patients must be 1-30 years of age with solid malignant tumors refractory to standard
A Phase I dose escalation study with 4 planned dose levels of lexatumumab starting at 30% of
the adult MTD and escalating up to 100% of the adult MTD, followed by a second dose
escalation using five lexatumumab dose levels in patients concomitantly receiving interferon
Three (expanded to six if DLT occurs) patients will be enrolled at each dose level of
lexatumumab until the adult MTD is reached and 6 patients will be enrolled at the adult MTD
dose. The MTD cohort of lexatumumab alone and combined regimen will be expanded to include
12 patients, which should include a minimum of 6 patients less than or equal to 12 years of
age. Once 6 patients greater than 12 years of age have completed lexatumumab alone, new
patients greater than 12 years of age will be enrolled in the combined regimen. Similarly,
once 6 patients complete lexatumumab alone who are less than or equal to 12 years of age,
new patients less than or equal to 12 years of age will be enrolled in the combined regimen.
A final dose escalation of interferon gamma 1b will be performed with the maximum dose
level of lexatumumab, to a dose level wherein archival tissue demonstrated upregulation of
Primary Purpose: Treatment
To determine the tolerance of the adult maximum tolerated dose and dose limiting toxicities of lexatumumab in patients with refractory pediatric solid tumors.
Crystal L Mackall, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|National Cancer Institute (NCI), 9000 Rockville Pike||Bethesda, Maryland 20892|