Phase 1 trial of ontuxizumab (MORAb-004) in children with relapsed or refractory solid tumors: A report from the Children's Oncology Group Phase 1 Pilot Consortium (ADVL1213)

Abstract

Background: Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation.

Methods: Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation.

Results: Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg.

Conclusion: Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults.

Trial registration: ClinicalTrials.gov NCT01748721.

Keywords: ontuxizumab; phase 1; solid tumors.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors do not have any relevant or important affiliations to disclose.

© 2018 Wiley Periodicals, Inc.

Figures

Figure 1

A. Individual endosialin plasma levels. B. Individual PDGFRβ plasma levels. Subjects treated at Dose Level 1 (4 mg/kg) represented with ■ and ······; Subjects treated at Dose Level 2 (8 mg/kg) represented with ◆ and _ _ _; Subjects treated at Dose Level 3 (12 mg/kg) represented with ● and ___. Subjects with stable disease indicated in red. Subjects who received 3 cycles of therapy indicated in black. All other subjects with PD after cycle 1 depicted in grey.