HGS-ETR2 to Treat Children With Solid Tumors
- HGS-ETR2 is a monoclonal antibody, produced in the laboratory from human genes.
- HGS-ETR2 targets a protein called the TRAIL receptor that is located on the surface of some tumor cells. When the TRAIL receptor is activated, it can cause the tumor cell to self-destruct.
- To determine the highest dose of HGS-ETR2 that can be given safely in children and young adults with cancer.
- To study the pharmacology (how the body handles the drug) of HGS-ETR2 by measuring the amount of drug in the bloodstream over time before and after a dose is given to the patient.
- To determine if HGS-ETR2 can stop or slow tumor growth.
- To determine whether proteins in tumor tissue before treatment can predict whether the tumor will respond to HGS-ETR2 therapy.
-Patients 1 to 21 years of age with solid cancers that do not respond to standard therapy.
- HGS-ETR2 is given through a vein (intravenously, IV) once every 14 days. Each treatment cycle is 28 days long and consists of two doses of HGS-ETR2.
- The dose of HGS-ETR2 is increased in successive small groups of patients until the maximum tolerated dose (highest dose with acceptable side effects) is determined.
- During the treatment period, patients have a physical examination at least once a week, and routine blood tests at least twice a week. These tests are done less frequently in later treatment cycles.
- Additional blood samples are drawn for immunology and pharmacology studies.
- Tests to monitor the size of the tumor (X-rays, CT scans, MRI, PET scans) are done periodically throughout the treatment period.
- Patients may continue to receive HGS-ETR2 until unacceptable side effects develop or the tumor grows.
|Ewing's Sarcoma Osteosarcoma Neuroblastoma Rhabdomyosarcoma||Drug: Lexatumumab alone Drug: Lexatumumab in combination Drug: Interferon gamma 1b in combination Drug: Gamma 1b potential expansion||Phase 1|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase I Trial of Monoclonal Antibody HGS-ETR2 (Lexatumumab) With or Without Interferon Gamma in Patients With Refractory Pediatric Solid Tumors|
- Asult MTD and DLTs of lexatumumab [ Time Frame: 6 months ]
- MTD of lexatumumab w/interferon gamma 1b [ Time Frame: 6 months ]
- Pharmacokinetics [ Time Frame: 2 years ]
- Tumor response rate [ Time Frame: 2 years ]
- Correlation of immunohistochemical expression of pro-apoptotic proteins with response to therapy [ Time Frame: 2 years ]
- Determine if anti-HGS-ETR2 antibodies are produced [ Time Frame: 2 years ]
|Study Start Date:||December 4, 2006|
|Study Completion Date:||October 9, 2015|
|Primary Completion Date:||April 28, 2011 (Final data collection date for primary outcome measure)|
Lexatumumab alone dose escalation
Drug: Lexatumumab alone
Dose escalation : 3mg/kg, 5mg/kg, 8mg/kg, 10mg/kg
Lexatumumab with interferon - dose escalation
Drug: Lexatumumab in combination
Dose escalation : 1mg/kg, 3mg/kg, 5mg/kg, 8mg/kg, 10mg/kgDrug: Interferon gamma 1b in combination
Dosing at the following for each lexatumumab dose level: .75mcg/m2/dose and 25mcg/m2/dose
Lexatumumab 10mg/kg with interferon expansion at
Drug: Lexatumumab in combination
Dose escalation : 1mg/kg, 3mg/kg, 5mg/kg, 8mg/kg, 10mg/kgDrug: Gamma 1b potential expansion
Potential expansion (at 10mg/kg lexatumumab): 1.5mcg/m2/dose and 50mcg/m2/dose
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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 therapy.
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 gamma 1b.
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 caspase 8.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00428272
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Crystal L Mackall, M.D.||National Cancer Institute (NCI)|