Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors

Abstract

Purpose: Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors.

Patients and methods: This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors.

Results: Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response.

Conclusion: Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.

Trial registration: ClinicalTrials.gov NCT00428272.

Fig 1.

Immunohistochemical analysis of archived tissues. Scores were calculated based on intensity (0, 1, 2, or 3) multiplied by the grade corresponding to the percent of positive cells (grade 0 [0% to 1%], grade 1 [2% to 10%], grade 2 [11% to 50%], grade 3 [51% to 100%]). Maximum score of 9 when 3+ in > 50% of cells, as shown in top example. ESFT, Ewing sarcoma family of tumors; met, metastasis; n.d., not done; osteo, osteosarcoma; TR1, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 1; TR2, TRAIL receptor 2.

Fig 2.

Prolonged clinical benefit after administration of lexatumumab 10 mg/kg in a 16-year-old patient with osteosarcoma of the chest wall. (A) Baseline positron emission tomography (PET)/computed tomography (CT) in patient with cough, shortness of breath, dyspnea on exertion, and chest wall pain. (B) PET/CT 6 months off therapy after 24 months of therapy, with no respiratory complaints or pain. (C) TR2 staining on archived osteosarcoma tissue. TR2, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2.

Fig 3.

Clinical activity with biomarker response in first cycle in a 2-year-old patient with hepatoblastoma. (A) Computed tomography with metastasis outlined in yellow. (B) Follow-up imaging after two doses, with 24% reduction in longest diameter and 54% reduction in volume by three-dimensional volumetric assessment. (C) Alpha fetoprotein decline over first cycle (arrows indicate lexatumumab administration).

Fig 4.

Regression of nontarget lesion in a recently irradiated field, with progressive disease outside the radiation field. (A) TR2 staining on archival tissue from patient age 16 years metastatic recurrent Ewing sarcoma; (B) lung metastasis (outlined in yellow) and prior field of radiation (red dashed line); (C) disappearance of lung metastasis within prior radiation field after three cycles of lexatumumab but concurrent growth of tumor outside radiation field (lower panel).

Fig A1.

Pharmacokinetics of lexatumumab in children and adolescents.